Oncology Intelligence

Prostate Cancer
Prostate cancer forms in the prostate, usually in older men. The median age at diagnosis is 72 years.
There are approximately 220 thousand new cases of prostate cancer each year in the US, about 165 new cases diagnosed per 100,000 men. For the last decade, incidence rates were stable in men younger than 65 and decreased by about 3% per year in those 65 and older.
Over 95% of prostate cancers are adenocarcinomas, the rest are small-cell tumors, Intralobular acinar carcinomas, ductal carcinomas, clear cell carcinomas, and mucinous carcinomas.
There are approximately 29 thousand deaths from prostate cancer in the US each year. Due to the widespread PSA screening in the United States, more than 90% of all PCs are diagnosed at an early stage. Prostate cancer may be cured when localized, and it frequently responds to treatment when widespread. The 5-year relative survival rate for men diagnosed in the United States in the last decade with local or regional disease was 100%, and the rate for distant disease was 28.7%. Poorly differentiated tumors are more likely to have metastasized before diagnosis and are associated with a poorer prognosis. Elevations of serum acid phosphatase are associated with poor prognosis in both localized and disseminated disease.
Advances in the treatment of prostate cancer include new surgical approaches and improvements in radiotherapy. Advances in hormonal therapy for prostate cancer include GnRH agonists, which inhibit the pituitary glands ability to stimulate the testes to make testosterone. GnRH agonists include leuprolide, goserelin, triptorelin, and histrelin. Additional male hormone based prostate cancer drugs include degarelix, flutamide, bicalutamide, nilutamide, and ketoconazole. Drugs approved for prostate cancer include: abiraterone, bicalutamide, cabazitaxel, degarelix, docetaxel, enzalutamide, goserelin, leuprolide, prednisone, Ra 223, and Sipuleucel-T.
Historic & ongoing prostate clinical trials
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Low β2-adrenergic receptor level may promote development of castration resistant prostate cancer and altered steroid metabolism Braadland, Peder; Grytli, Helene Hartvedt; Ramberg, Håkon Andre; Katz, Betina; Kellmann, Ralf; Gauthier-Landry, louis; Fazli, Ladan; Krobert, Kurt Allen; Wang, Wanzhong; Levy, Finn Olav; Bjartell, Anders; Berge, Viktor; Rennie, Paul S.; Mellgren, Gunnar; Mælandsmo, Gunhild; Svindland, Aud; Barbier, Olivier; Tasken, Kristin Austlid Journal article The underlying mechanisms responsible for the development of castration-resistant prostate cancer (CRPC) in patients who have undergone androgen deprivation therapy are not fully understood. This is the first study to address whether β2-adrenergic receptor (ADRB2)- mediated signaling may affect CRPC progression in vivo. By immunohistochemical analyses, we observed that low levels of ADRB2 is associated with a more rapid development of CRPC in a Norwegian patient cohort. To elucidate mechanisms by which ADRB2 may affect CRPC development, we stably transfected LNCaP cells with shRNAs to mimic low and high expression of ADRB2. Two UDP-glucuronosyltransferases, UGT2B15 and UGT2B17, involved in phase II metabolism of androgens, were strongly downregulated in two LNCaP shADRB2 cell lines. The low-ADRB2 LNCaP cell lines displayed lowered glucuronidation activities towards androgens than high-ADRB2 cells. Furthermore, increased levels of testosterone and enhanced androgen responsiveness were observed in LNCaP cells expressing low level of ADRB2. Interestingly, these cells grew faster than high-ADRB2 LNCaP cells, and sustained their low glucuronidation activity in castrated NOD/SCID mice. ADRB2 immunohistochemical staining intensity correlated with UGT2B15 staining intensity in independent TMA studies and with UGT2B17 in one TMA study. Similar to ADRB2, we show that low levels of UGT2B15 are associated with a more rapid CRPC progression. We propose a novel mechanism by which ADRB2 may affect the development of CRPC through downregulation of UGT2B15 and UGT2B17.
5:17 AM|Current Medicinal Chemistry-Anti-Cancer Agents (Volume 5 - Issue 6)|Labels: prostate cancer
Prostate cancer is the most common cancer amongst men in the USA and the second most common malignant cause of male death worldwide after lung cancer. The life time risk of having microscopic evidence of prostate cancer for a 50 year old man is 42%. Prostate cancer is thus becoming an increasingly significant global health problem in terms of mortality, morbidity, as well as economically. This review, discusses current medical therapeutic options for prostate cancer including traditional treatments using luteinising hormone releasing analogues (LHRH), anti-androgens and estrogen treatments, and the use of novel drugs directed against molecular targets considered important in oncogenesis and metastasis. Prostate cancer chemoprevention using 5a-reductase inhibitors and the role of gene therapy are also considered.
10:47 AM|Luk, I. S. U., Shrestha, R., Xue, H., Wang, Y., Zhang, F., Lin, D., Haegert, A., Wu, R., Dong, X., Collins, C. C., Zoubeidi, A., Gleave, M. E., Gout, P. W., Wang, Y.|Clinical Cancer Research Online First Articles|Labels: prostate cancer

Purpose: Enzalutamide (ENZ) resistance has emerged as a major problem in the management of castration-resistant prostate cancer (CRPC). Research on therapy resistance of CRPCs has primarily focussed on the androgen receptor pathway. In contrast, there is limited information on anti-apoptotic mechanisms that may facilitate the treatment resistance. The Inhibitor of Apoptosis Protein (IAP) family is well recognized for its role in promoting treatment resistance of cancers by inhibiting drug-induced apoptosis. Here we examined whether BIRC6, an IAP family member, has a role in ENZ resistance of CRPCs and could provide a therapeutic target for ENZ-resistant CRPC. Experimental Design: Use of ENZ-resistant CRPC models: (i) the transplantable, first high-fidelity LTL-313BR patient-derived ENZ-resistant CRPC tissue xenograft line showing primary ENZ resistance, (ii) MR42D and MR49F CRPC cells/xenografts showing acquired ENZ resistance. Specific BIRC6 downregulation in these models was produced using a BIRC6-targeting antisense oligonucleotide (ASO-6w2). Gene expression was determined by qPCR and gene expression profiling. Molecular pathways associated with growth inhibition were assessed via gene enrichment analysis. Results: Of eight IAPs examined, BIRC6 was the only one showing elevated expression in both ENZ-resistant CRPC models. Treatment with ASO-6w2 markedly suppressed growth of LTL-313BR xenografts and increased tumour apoptosis, without inducing major host toxicity. Pathway enrichment analysis indicated GPCR and matrisome signalling were most significantly altered pathways. Furthermore, ASO-6w2 inhibited expression of pro-survival genes that were up-regulated in the LTL-313BR line. Conclusions: BIRC6-targeting inhibited growth of ENZ-resistant CRPC models and may represent a new option for clinical treatment of advanced, ENZ-resistant prostate cancer.

Wednesday, September 21, 2016 11:21 PM|Oncology|Labels: prostate cancer
The availability of new drugs capable of improving the overall survival of patients with metastatic castration-resistant prostate cancer has led to the possibility of using them sequentially in the hope of obtaining a cumulative survival benefit. The new agents have already been administered as third-line treatments in patients who have previously received them as second line in everyday clinical practice, but the efficacy of this practice is not yet supported by clinical trial data, and evidence of possible cross-resistance has reinforced the debate concerning the best sequence to use in order to maximise the benefit. Furthermore, the situation is further complicated by the possibility of administering new hormonal agents to chemotherapy-naïve patients, and novel chemotherapeutic agents to hormone-sensitive patients. This article critically reviews the available data concerning the sequential use of new drugs, and discusses the real evidence concerning their optimal positioning in the therapeutic strategy of metastatic castration-resistant prostate cancer.
Wednesday, September 21, 2016 1:42 PM|The Medical News|Comments|Labels: prostate cancer, biomarker diagnostic
While searching for a non-invasive way to detect prostate cancer cells circulating in blood, Duke Cancer Institute researchers have identified some blood markers associated with tumor resistance to two common hormone therapies.
Wednesday, September 21, 2016 4:18 AM|Elsevier|JournalTOCs API - Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (50 articles)|Labels: prostate cancer

Endogenous TRPV1 stimulation leads to the activation of the inositol phospholipid pathway necessary for sustained Ca2+ oscillations

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Vol. , No. (2016) pp. -
Publication date: Available online 20 September 2016 Source:Biochimica et Biophysica Acta (BBA) - Molecular Cell Research Author(s): László Pecze, Walter Blum, Thomas Henzi, Beat Schwaller Sensory neuron subpopulations as well as breast and prostate cancer cells express functional transient receptor potential vanilloid type 1 (TRPV1) ion channels; however little is known how TRPV1 activation leads to biological responses. Agonist-induced activation of TRPV1 resulted in specific spatiotemporal patterns of cytoplasmic Ca2+ signals in breast and prostate cancer-derived cells. Capsaicin (CAPS; 50μM) evoked intracellular Ca2+ oscillations and/or intercellular Ca2+ waves in all cell lines. As evidenced in prostate cancer Du 145 cells, oscillations were largely dependent on the expression of functional TRPV1 channels in the plasma membrane, phospholipase C activation and on the presence of extracellular Ca2+ ions. Concomitant oscillations of the mitochondrial matrix Ca2+ concentration resulted in mitochondria energization evidenced by increased ATP production. CAPS-induced Ca2+ oscillations also occurred in a subset of sensory neurons, yet already at lower CAPS concentrations (1μM). Stimulation of ectopically expressed TRPV1 channels in CAPS-insensitive NIH-3T3 cells didn't provoke CAPS-triggered Ca2+ oscillations; rather it resulted in low-magnitude, long-lasting elevations of the cytosolic Ca2+ concentration. This indicates that sole TRPV1 activation is not sufficient to generate Ca2+ oscillations. Instead the initial TRPV1-mediated signal leads to the activation of the inositol phospholipid pathway. This in turn suffices to generate a biologically relevant frequency-modulated Ca2+ signal.

Tuesday, September 20, 2016 1:49 PM|Google News on 'cancer for a feed'|Labels: prostate cancer

Forward March: Push Continues for Immunotherapy in Prostate Cancer
In the area of hormonal therapy, a staple of prostate cancer care, new drugs including apalutamide and ODM-201 are being explored. Further, anti-angiogenesis drugs, which kill the blood vessels that feed a tumor, are being explored by scientists as a ...

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Monday, September 19, 2016 12:22 PM|Onclive Articles|Labels: prostate cancer
A treatment recommendation based on reduced prostate-specific antigen failure observed from early results of randomized controlled trials is not likely to prolong survival in men with moderate-to-severe comorbidities.
Friday, September 16, 2016 5:02 PM|els-cm|Advanced prostate cancer - Metastatic prostate cancer resource centre|Labels: prostate cancer, clinical trial
Abstract Enzalutamide significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) among men with chemotherapy-naïve metastatic castration-resistant prostate cancer at the prespecified interim analysis of PREVAIL, a...
Friday, September 16, 2016 5:02 PM|els-cm|Advanced prostate cancer - Metastatic prostate cancer resource centre|Labels: prostate cancer
The objective of this study was to analyze the safety and efficacy of the (177)Lu-labeled DOTAGA-based prostate-specific membrane antigen(PSMA) ligand (177)Lu-DOTAGA-(I-y)fk(Sub-KuE) ((177)Lu-PSMA) in patients with metastatic castration-resistant...
Friday, September 16, 2016 5:02 PM|els-cm|Advanced prostate cancer - Metastatic prostate cancer resource centre|Labels: prostate cancer
PURPOSE: The purpose of this study was to evaluate the efficacy and safety of a novel theranostic agent, 177 Lu-DKFZ-PSMA-617 therapy in metastatic castration resistant prostate cancer (mCRPC). METHODS: Thirty-one mCRPC patients with progressive...
Friday, September 16, 2016 5:02 PM|els-cm|Advanced prostate cancer - Metastatic prostate cancer resource centre|Labels: prostate cancer, cost
OBJECTIVE: To calculate costs per median overall survival (OS) month in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate plus prednisone (AA + P) or enzalutamide. METHODS :...
Friday, September 16, 2016 4:27 PM|Wei Zhang, Yan Meng, Na Liu, Xiao-Fei Wen, Tao Yang|International Journal of Biological Sciences|Labels: prostate cancer

Prostate cancer (PCa) remains the most prevalent malignancy among males in the western world. Though hormonal therapies through chemical or surgical castration have been proposed many years ago, heretofore, such mainstay for the treatment on advanced PCa has not fundamentally changed. These therapeutic responses are temporary and most cases will eventually undergo PCa recurrence and metastasis, or even progress to castration-resistant prostate cancer (CRPC) due to persistent development of drug resistance. Prostate cancer stem cells (PCSCs) are a small population of cells, which possess unlimited self-renewal capacities, and can regenerate tumorigenic progenies, and play an essential role in PCa therapy resistance, metastasis and recurrence. Nowadays advanced progresses have been made in understanding of PCSC properties, roles of androgen receptor signaling and ATP-binding cassette sub-family G member 2 (ABCG2), as well as roles of genomic non-coding microRNAs and key signaling pathways, which have led to the development of novel therapies which are active against chemoresistant PCa and CRPC. Based on these progresses, this review is dedicated to address mechanisms underlying PCa chemoresistance, unveil crosstalks among pivotal signaling pathways, explore novel biotherapeutic agents, and elaborate functional properties and specific roles of chemoresistant PCSCs, which may act as a promising target for novel therapies against chemoresistant PCa.

Friday, September 16, 2016 4:27 PM|Yanqing Huang, Chengliu Jin, Tomoaki Hamana, Junchen Liu, Cong Wang, Lei An, Wallace L. McKeehan, Fen Wang|International Journal of Biological Sciences|Labels: FGFR, prostate cancer

Bone metastasis is the major cause of morbidity and mortality of prostate cancer (PCa). Fibroblast growth factor 9 (FGF9) has been reported to promote PCa bone metastasis. However, the mechanism by which overexpression of FGF9 promotes PCa progression and metastasis is still unknown. Herein, we report that transgenic mice forced to express FGF9 in prostate epithelial cells (F9TG) developed high grade prostatic intraepithelial neoplasia (PIN) in an expression level- and time-dependent manner. Moreover, FGF9/TRAMP bigenic mice (F9TRAMP) grew advanced PCa earlier and had higher frequencies of metastasis than TRAMP littermates. We observed tumor microenvironmental changes including hypercellularity and hyperproliferation in the stromal compartment of F9TG and F9TRAMP mice. Expression of TGFβ1, a key signaling molecule overexpressed in reactive stroma, was increased in F9TG and F9TRAMP prostates. Both in vivo and in vitro data indicated that FGF9 promoted TGFβ1 expression via increasing cJun-mediated signaling. Moreover, in silico analyses showed that the expression level of FGF9 was positively associated with expression of TGFβ1 and its downstream signaling molecules in human prostate cancers. Collectively, our data demonstrated that overexpressing FGF9 in PCa cells augmented the formation of reactive stroma and promoted PCa initiation and progression.

Friday, September 16, 2016 4:27 PM|Esther Llop, Montserrat Ferrer-Batallé, Sílvia Barrabés, Pedro Enrique Guerrero, Manel Ramírez, Radka Saldova, Pauline M. Rudd, Rosa N. Aleixandre, Josep Comet, Rafael de Llorens, Rosa Peracaula|Theranostics|Labels: prostate cancer

New markers based on PSA isoforms have recently been developed to improve prostate cancer (PCa) diagnosis. However, novel approaches are still required to differentiate aggressive from non-aggressive PCa to improve decision making for patients.

PSA glycoforms have been shown to be differentially expressed in PCa. In particular, changes in the extent of core fucosylation and sialylation of PSA N-glycans in PCa patients compared to healthy controls or BPH patients have been reported. The objective of this study was to determine these specific glycan structures in serum PSA to analyze their potential value as markers for discriminating between BPH and PCa of different aggressiveness.

In the present work, we have established two methodologies to analyze the core fucosylation and the sialic acid linkage of PSA N-glycans in serum samples from BPH (29) and PCa (44) patients with different degrees of aggressiveness. We detected a significant decrease in the core fucose and an increase in the α2,3-sialic acid percentage of PSA in high-risk PCa that differentiated BPH and low-risk PCa from high-risk PCa patients. In particular, a cut-off value of 0.86 of the PSA core fucose ratio, could distinguish high-risk PCa patients from BPH with 90% sensitivity and 95% specificity, with an AUC of 0.94. In the case of the α2,3-sialic acid percentage of PSA, the cut-off value of 30% discriminated between high-risk PCa and the group of BPH, low-, and intermediate-risk PCa with a sensitivity and specificity of 85.7% and 95.5%, respectively, with an AUC of 0.97. The latter marker exhibited high performance in differentiating between aggressive and non-aggressive PCa and has the potential for translational application in the clinic.

Friday, September 16, 2016 4:27 PM|Kristell L.S. Chatalic, Sandra Heskamp, Mark Konijnenberg, Janneke D.M. Molkenboer-Kuenen, Gerben M. Franssen, Marian C. Clahsen-van Groningen, Margret Schottelius, Hans-Jürgen Wester, Wytske M. van Weerden, Otto C. Boerman, Marion de Jong|Theranostics|Labels: prostate cancer

Prostate-specific membrane antigen (PSMA) is a well-established target for nuclear imaging and therapy of prostate cancer (PCa). Radiolabeled small-molecule PSMA inhibitors are excellent candidates for PCa theranostics—they rapidly and efficiently localize in tumor lesions. However, high tracer uptake in kidneys and salivary glands are major concerns for therapeutic applications. Here, we present the preclinical application of PSMA I&T, a DOTAGA-chelated urea-based PSMA inhibitor, for SPECT/CT imaging and radionuclide therapy of PCa. 111In-PSMA I&T showed dose-dependent uptake in PSMA-expressing tumors, kidneys, spleen, adrenals, lungs and salivary glands. Coadministration of 2-(phosphonomethyl)pentane-1,5-dioic acid (2-PMPA) efficiently reduced PSMA-mediated renal uptake of 111In-PSMA I&T, with the highest tumor/kidney radioactivity ratios being obtained using a dose of 50 nmol 2-PMPA. SPECT/CT clearly visualized subcutaneous tumors and sub-millimeter intraperitoneal metastases; however, high renal and spleen uptake in control mice (no 2-PMPA) interfered with visualization of metastases in the vicinity of those organs. Coadministration of 2-PMPA increased the tumor-to-kidney absorbed dose ratio during 177Lu-PSMA I&T radionuclide therapy. Hence, at equivalent absorbed dose to the tumor (36 Gy), coinjection of 2-PMPA decreased absorbed dose to the kidneys from 30 Gy to 12 Gy. Mice injected with 177Lu-PSMA I&T only, showed signs of nephrotoxicity at 3 months after therapy, whereas mice injected with 177Lu-PSMA I&T + 2-PMPA did not. These data indicate that PSMA I&T is a promising theranostic tool for PCa. PSMA-specific uptake in kidneys can be successfully tackled using blocking agents such as 2-PMPA.

Friday, September 16, 2016 10:23 AM|Kristine M Wadosky, Shahriar Koochekpour|International Journal of Biological Sciences|Labels: prostate cancer

Patients with localized prostate cancer (PCa) have several therapeutic options with good prognosis. However, survival of patients with high-risk, advanced PCa is significantly less than patients with early-stage, organ-confined disease. Testosterone and other androgens have been directly linked to PCa progression since 1941. In this review, we chronicle the discoveries that led to modern therapeutic strategies for PCa. Specifically highlighted is the biology of androgen receptor (AR), the nuclear receptor transcription factor largely responsible for androgen-stimulated and castrate-recurrent (CR) PCa. Current PCa treatment paradigms can be classified into three distinct but interrelated categories: targeting AR at pre-receptor, receptor, or post-receptor signaling. The continuing challenge of disease relapse as CR and/or metastatic tumors, destined to occur within three years of the initial treatment, is also discussed. We conclude that the success of PCa therapies in the future depends on targeting molecular mechanisms underlying tumor recurrence that still may affect AR at pre-receptor, receptor, and post-receptor levels.

Thursday, September 15, 2016 7:51 PM|Lu Yang, Liang Gao, Yongji Chen, Zhuang Tang, Yuchun Zhu, Ping Han, Xiang Li, Qiang Wei|International Journal of Medical Sciences|Labels: CXCRX, prostate cancer

Background: Chemokine and chemokine receptors could have played an important role in tumor angiogenesis and distant metastasis. The mechanism of inflammation, expression and function of chemokines and chemokine receptors in benign prostatic hyperplasia (BPH) and prostate cancer (PCa) remain unclear. The purpose of present study is to detect differential expression and function of chemokines and chemokine receptors (CCRs) in BPH and PCa.

Methods: BPH-1 and peripheral blood mononuclear cells (PBMCs) were co-cultured in Transwell chambers, and human normal prostate (NP) tissues, BPH tissues and PCa tissues were collected. CCR gene-chips were used to analyze and compare the differential expression of CCRs in BPH-1 cells, BPH-1 cells co-cultured with PBMCs, and LNCaP cells. The differential expression of CCRs was detected and validated using real-time PCR, western blotting and immunofluorescence (IF). The proliferation of LNCaP cells was also investigated after the knockdown CXCR5.

Results: Results of gene-chips indicated that there was low or no expression of CCR10, CXCR1, CXCR3 and CXCR5 in BPH-1 cells, whereas the expression of these receptors in BPH-1 cells was increased by PBMCs, and the expression was high in LNCaP cells. Furthermore, real-time PCR and western blotting confirmed the above mentioned results. IF verified no or low expression of CXCR1, CXCR3 and CXCR5 in NP tissues, low or moderate expression in BPH and high expression in PCa. However, CCR10 was not expressed at detectable levels in the three groups. The growth and proliferation of LNCaP cells was markedly inhibited after down-regulation of CXCR5.

Conclusions: PCa cells expressed high levels of CCR10, CXCR1, CXCR3 and CXCR5. Although BPH cells did not express these factors, their expression was up-regulated when BPH-1 cells were incubated with inflammatory cells. Finally, down-regulation of CXCR5 inhibited the growth and proliferation of LNCaP cells.

Thursday, September 15, 2016 7:51 PM|Chia-Hung Liu, Wan-Chun Tang, Peik Sia, Chi-Chen Huang, Pei-Ming Yang, Ming-Heng Wu, I-Lu Lai, Kuen-Haur Lee|International Journal of Medical Sciences|Labels: prostate cancer

Background: Over 70% of cancer metastasis from prostate cancer develops bone metastases that are not sensitive to hormonal therapy, radiation therapy, or chemotherapy. The epithelial-to-mesenchymal transition (EMT) genetic program is implicated as a significant contributor to prostate cancer progression. As such, targeting the EMT represents an important therapeutic strategy for preventing or treating prostate cancer metastasis. Berberine is a natural alkaloid with significant antitumor activities against many types of cancer cells. In this study, we investigated the molecular mechanism by which berberine represses the metastatic potential of prostate cancer.

Methods: The effects of berberine on cell migration and invasion were determined by transwell migration assay and Matrigel invasion assay. Expressions of EMT-related genes were determined by an EMT PCR Array and a quantitative RT-PCR. The prognostic relevance of berberine's modulation of EMT-related genes in prostate cancer was evaluated using Kaplan-Meier survival analysis.

Results: Berberine exerted inhibitory effects on the migratory and invasive abilities of highly metastatic prostate cancer cells. These inhibitory effects of berberine resulted in significant repression of a panel of mesenchymal genes that regulate the developmental EMT. Among EMT-related genes downregulated by berberine, high BMP7, NODAL and Snail gene expressions of metastatic prostate cancer tissues were associated with shorter survival of prostate cancer patients and provide potential therapeutic interventions.

Conclusions: We concluded that berberine should be developed as a pharmacological agent for use in combination with other anticancer drug for treating metastatic prostate cancer.

Thursday, September 15, 2016 5:47 PM|Latest Science News -- ScienceDaily|Labels: prostate cancer
For men with early stage prostate cancer, there is no difference in mortality rates following active monitoring, surgery or RT, ten-year findings from a trial indicate. Moreover, cancer-specific deaths at ten years following diagnosis averaged only one percent for all men enrolled in the trial.
Thursday, September 15, 2016 7:42 AM|T. L.|JournalTOCs API - Clinical Cancer Research (27 articles)|Labels: prostate cancer

AR and AR-V7 RISH in Prostate Cancer
Guedes, L. B Morais, C. L, Almutairi, F, Haffner, M. C, Zheng, Q, Isaacs, J. T, Antonarakis, E. S, Lu, C, Tsai, H, Luo, J, De Marzo, A. M, Lotan, T. L.
Clinical Cancer Research, Vol. 22, No. 18 (2016) pp. 4651 - 4663
Purpose: RNA expression of androgen receptor splice variants may be a biomarker of resistance to novel androgen deprivation therapies in castrate-resistant prostate cancer (CRPC). We analytically validated an RNA in situ hybridization (RISH) assay for total AR and AR-V7 for use in formalin-fixed paraffin-embedded (FFPE) prostate tumors. Experimental Design: We used prostate cell lines and xenografts to validate chromogenic RISH to detect RNA containing AR exon 1 (AR-E1, surrogate for total AR RNA species) and cryptic exon 3 (AR-CE3, surrogate for AR-V7 expression). RISH signals were quantified in FFPE primary tumors and CRPC specimens, comparing to known AR and AR-V7 status by IHC and RT-PCR. Results: The quantified RISH results correlated significantly with total AR and AR-V7 levels by RT-PCR in cell lines, xenografts, and autopsy metastases. Both AR-E1 and AR-CE3 RISH signals were localized in nuclear punctae in addition to the expected cytoplasmic speckles. Compared with admixed benign glands, AR-E1 expression was significantly higher in primary tumor cells with a median fold increase of 3.0 and 1.4 in two independent cohorts (P < 0.0001 and P = 0.04, respectively). While AR-CE3 expression was detectable in primary prostatic tumors, levels were substantially higher in a subset of CRPC metastases and cell lines, and were correlated with AR-E1 expression. Conclusions: RISH for AR-E1 and AR-CE3 is an analytically valid method to examine total AR and AR-V7 RNA levels in FFPE tissues. Future clinical validation studies are required to determine whether AR RISH is a prognostic or predictive biomarker in specific clinical contexts. Clin Cancer Res; 22(18); 4651&ndash;63. &copy;2016 AACR.

Wednesday, September 14, 2016 6:37 PM|Oncology|Labels: PD-1/PD-L1, prostate cancer
Prostate cancer was one of the first cancer types where FDA (Food and Drug Administration) approval was granted to a cancer vaccine, sipuleucel-T, in the metastatic setting for asymptomatic or minimally symptomatic patients. This marked the beginning of the era of immunotherapies in cancer and stimulated the interest to develop other immune-based novel agents. In addition to sipuleucel-T vaccine, pox viral-based vaccine and personalized peptide vaccine are also being investigated in prostate cancer. Other agents that modulate the tumor microenvironment to enhance the immune response against the prostate cancer cells is also being developed. Immune checkpoint inhibitors such as ipilimumab, anti-PD-1 monoclonal antibody (programmed cell death-1), and Indoleamine 2,3-dioxygenase (IDO) inhibitors have shown some promise in this field. However, similar to sipuleucel-T vaccine, the preliminary data reflects the efficacy of these to be limited to mCRPC patients with favorable risk factors without any visceral disease. More clinical trials are needed to identify the group of patients with mCRPC that would benefit from immunotherapy. In this article we review the role of immune-based therapies including vaccines and immune checkpoint inhibitors in mCRPC.
Wednesday, September 14, 2016 6:00 PM|Milan S. Geybels, Jonathan L. Wright, Marina Bibikova, Brandy Klotzle, Jian-Bing Fan, Shanshan Zhao, Ziding Feng, Elaine A. Ostrander, Daniel W. Lin, Peter S. Nelson and Janet L. Stanford|Articles: MD Anderson Cancer Center|Labels: prostate cancer
Identifying the subset of patients with clinically localized prostate cancer (PCa) at the highest risk of recurrence remains challenging, and better prognostic markers are needed. Gleason score is the best pre...
Wednesday, September 14, 2016 5:53 PM|Xiang Li, Xiang Li, Jiaxiong Wang, Zaiyuan Ye, Ji-Cheng Li|International Journal of Biological Sciences|Labels: prostate cancer, clinical trial

Background: Oridonin (ORI) could inhibit the proliferation and induce apoptosis in various cancer cell lines. However, the mechanism is not fully understood.

Methods: Human prostate cancer (HPC) cells were cultured in vitro and cell viability was detected by the CCK-8 assay. The ultrastructure changes were observed under transmission electron microscope (TEM). Chemical staining with acridine orange (AO), MDC or DAPI was used to detect acidic vesicular organelles (AVOs) and alternation of DNA. Expression of LC3 and P21 was detected by Western Blot. Apoptotic rates and cell cycle arrest were detected by FACS.

Results: Our study demonstrated that after ORI treatment, the proliferations of human prostate cancer (HPC) cell lines PC-3 and LNCaP were inhibited in a concentration and time-dependent manner. ORI induced cell cycle arrest at the G2/M phase. A large number of autophagosomes with double-membrane structure and acidic vesicular organelles (AVOs) were detected in the cytoplasm of HPC cells treated with ORI for 24 hours. ORI resulted in the conversion of LC3-I to LC3-II and recruitment of LC3-II to the autophagosomal membranes. Autophagy inhibitor 3-methyladenine (3-MA) reduced AVOs formation and inhibited LC3-I to LC3-II conversion. At 48 h, DNA fragmentation, chromatin condensation and disappearance of surface microvilli were detected in ORI-treated cells. ORI induced a significant increase in the number of apoptotic cells (PC-3: 5.4% to 27.0%, LNCaP: 5.3% to 31.0%). Promoting autophagy by nutrient starvation increased cell viability, while inhibition of autophagy by 3-MA promoted cell death. The expression of P21 was increased by ORI, which could be completely reversed by the inhibition of autophagy.

Conclusions: Our findings indicated that autophagy occurred before the onset of apoptosis and protected cancer cells in ORI-treated HPC cells. P21 was involved in ORI-induced autophagy and apoptosis. Our results provide an experimental basis for understand the anti-tumor mechanism of ORI as treatment for prostate cancer.

Wednesday, September 14, 2016 5:53 PM|Keitaro Matsuo|Articles : Journal of Carcinogenesis as on May 20, 2016)|Labels: prostate cancer
Hiroe Ono, Dai Chihara, Fumiko Chiwaki, Kazuyoshi Yanagihara, Hiroki Sasaki, Hiromi Sakamoto, Hideo Tanaka, Teruhiko Yoshida, Norihisa Saeki, Keitaro Matsuo

Journal of Carcinogenesis 2013 12(1):4-4

Background: Prostate stem cell antigen (PSCA), an organ-dependent tumor suppressor, is down regulated in gallbladder cancer (GBC). It is anticipated that the missense allele C of the single nucleotide polymorphism (SNP) rs2294008 (T/C) in the translation initiation codon of the gene affects the gene's biological function and has some influence on GBC susceptibility. We examined the biological effect of the C allele on the function of the gene and the relation between the C allele and GBC susceptibility. Materials and Methods: Functional analysis of the SNP was conducted by introducing PSCA cDNA harboring the allele to a GBC cell line TGBC- 1TKB and performing colony formation assays in vitro and tumor formation assays in mice. The effect on transcriptional regulation was assessed by reporter assays. The association study was conducted on 44 Japanese GBC cases and 173 controls. Results: The PSCA cDNA harboring the C allele showed lower cell growth inhibition activity (20% reduction) than that with the T allele. Concordantly, when injected into subcutaneous tissues of mice, the GBC cell line stably expressing the cDNA with the C allele formed tumors of almost the same size as that of the control cells, but the cell line expressing the cDNA with the T allele showed slower growth. The upstream DNA fragment harboring the C allele had more transcriptional activity than that with the T allele. The C allele showed positive correlation to GBC but no statistical significant odds ratio (OR = 1.77, 95% confidence interval 0.85-3.70, P value = 0.127 in dominant model). Conclusions: The missense allele was shown to have a biological effect, attenuating antitumor activities of PSCA, and consequently it may be a potential risk for GBC development. An association study in a larger sample size may reveal a significant association between the allele and GBC.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: prostate cancer, clinical trial
This phase II trial is studying how well giving phenelzine sulfate together with docetaxel works in treating patients with prostate cancer with progressive disease after first-line therapy with docetaxel. Phenelzine sulfate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Phenelzine sulfate may also help docetaxel work better by making tumor cells more sensitive to the drug. Giving phenelzine sulfate together with docetaxel may kill more tumor cells.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: MET, VEGF, prostate cancer, clinical trial
This pilot clinical trial studies cabozantinib in treating men with hormone-resistant prostate cancer. Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth
This randomized phase II trial studies how well glycosylated recombinant human interleukin-7 (CYT107) after vaccine therapy works in treating patients with hormone-resistant prostate cancer that has spread to other areas of the body or has not responded to at least one type of treatment. Biological therapies, such as glycosylated recombinant human interleukin-7, may stimulate the immune system in different ways and stop tumor cells from growing. Vaccines made from white blood cells mixed with tumor proteins may help the body build an effective immune response to kill tumor cells. It is not yet known whether glycosylated recombinant human interleukin-7 works better with or without vaccine therapy in treating prostate cancer.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: AR, prostate cancer, clinical trial
This research study is evaluating a drug called enzalutamide in metastatatic castration resistant prostate cancer.Enzalutamide is already FDA approved for metastatic castration resistant prostate cancer after treatment with chemotherapy. The purpose of this study is to analyze features of tumor specimens sampled prior to therapy and at disease progression to determine why patients respond or stop responding to treatment with Enzalutamide. Prior chemotherapy is not a requirement of this trial. Enzalutamide is a drug designed to block the effects of male hormones in the body that may be helping prostate cancer to grow. It has already been approved by the FDA (the U.S. Food and Drug Administration) for patients with castration-resistant prostate cancer who have received prior chemotherapy. Additionally, this study will analyze features of tumor specimens sampled prior to therapy and at disease progression to determine why patients respond or stop responding to treatment with enzalutamide.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: prostate cancer, clinical trial
This phase I/II trial studies the side effects and best dose of cabazitaxel when given together with enzalutamide in treating patients with prostate cancer that has spread to other places in the body (metastatic) and has not responded to treatment with hormones (hormone-resistant). Drugs used in chemotherapy, such as cabazitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Androgen can cause the growth of prostate cancer cells. Hormone therapy using enzalutamide may fight prostate cancer by blocking the use of androgen by the tumor cells. Giving cabazitaxel together with enzalutamide may work better in treating metastatic, hormone-resistant prostate cancer.
Asymptomatic men with progressive metastatic CRPC post- treatment with abiraterone acetate (pre-chemotherapy for metastatic disease) will be treated on a randomized, multi-Institutional open label study to determine if treatment with intramuscular T given on a dose/schedule designed to result in rapid cycling from the polar extremes of supraphysiologic to near castrate levels [i.e. Bipolar Androgen Therapy (BAT)] will improve primary and secondary objectives vs. enzalutamide as standard therapy.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: BRCA, prostate cancer
This pilot clinical trial studies docetaxel and carboplatin in treating patients with prostate cancer that does not respond to treatment with hormones (hormone resistant) and that has spread from the primary site (place where it started) to other places in the body (metastatic). Drugs used in chemotherapy, such as docetaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: prostate cancer, clinical trial
This partially randomized phase I/II trial studies the side effects and how well sirolimus works when given together with docetaxel and carboplatin in treating patients with hormone-resistant prostate cancer that has spread to other places in the body. Biological therapies, such as sirolimus, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop tumor cells from growing. Drugs used in chemotherapy, such as docetaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving sirolimus together with docetaxel and carboplatin may kill more tumor cells.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: prostate cancer, clinical trial
This phase I trial studies the side effects and best dose of niclosamide when given together with enzalutamide in treating patients with androgen receptor splice variant-positive, castration resistant prostate cancer that has spread from the primary site to other places in the body. Androgens such as testosterone can cause the growth of prostate cancer cells. Drugs like enzalutamide block androgens from driving tumor growth; however, when androgen receptor splice variants are present, these drugs may not be effective. Niclosamide may decrease the amount of androgen receptor splice variant present within tumor cells, thus promoting the anti-tumor effects of enzalutamide. Giving niclosamide together with enzalutamide may be a better treatment for prostate cancer.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: prostate cancer, clinical trial
The purpose of this study is to compare overall survival in newly diagnosed metastatic prostate cancer patients randomly assigned to androgen deprivation therapy (ADT) + TAK-700 versus ADT + bicalutamide.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: AR, prostate cancer
The proposed clinical trial will study the effects of 12 months of therapy with ARN-509 alone, or in combination with an LHRH agonist (LHRHa), each compared to LHRHa alone, in men with a rapidly rising serum PSA after prior definitive local therapy for prostate cancer. The endpoints selected reflect measurable short term effects of androgen deprivation therapy (ADT), including quality of life and several metabolic parameters. In addition, the relative effect of each treatment strategy on PSA suppression as well as testosterone recovery (and subsequent PSA progression) after 12 months of therapy will be evaluated.
To determine if the addition of radium-223 dichloride to standard treatment is able to prolong life and to delay events specific for prostate cancer which has spread to the bone, such as painful fractures or bone pain which needs to be treated with an X-ray machine.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: prostate cancer, clinical trial
The study will be conducted in 2 Stages. The primary objective of Stage 1 of the study is to identify the maximum tolerated dose (MTD) of MOR209/ES414 administered intravenously to patients with mCRPC. Secondary objectives are to evaluate the tolerability, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, cytokine response, and clinical activity of MOR209/ES414. The primary objective of Stage 2 of the study is to evaluate the clinical activity of MOR209/ES414 in patients that have or have not received prior chemotherapy. Secondary objectives are to further characterize the safety profile, PK, PD, and immunogenicity of MOR209/ES414.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: prostate cancer, clinical trial
The goal of this clinical study is to determine the safety and efficacy of VT-464, a lyase-selective inhibitor of CYP17 and an androgen receptor antagonist, in patients with castration-resistant prostate cancer (CRPC) who have been previously treated with enzalutamide or abiraterone.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: prostate cancer, clinical trial
The study will evaluate the safety, pharmacokinetics and pharmacodynamics of increasing doses of a vaccine-based immunotherapy regimen for patients with prostate cancer.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: prostate cancer, clinical trial
The study will consist of 2 parts: Part I (Dose Escalation) and Part II (Dose Expansion). In Part I, patients will participate in single, multiple, and long-term dosing periods using EPI-506 to determine safety, pharmacokinetics, the maximum tolerated dose, and preliminary indications of anti-tumor activity. Part I is an open-label, adaptive 3 + 3 design, dose-escalation study. Up to six dose levels of EPI-506 will be studied, beginning at 80 mg/day. Patients may be allowed to escalate sequentially to a higher dose cohort after twelve weeks of dosing. In Part II, 3 patient populations; post-abiraterone metastatic castration-resistant prostate cancer (mCRPC) but enzalutamide-naïve, post-enzalutamide mCRPC but abiraterone-naïve, and post-abiraterone and enzalutamide mCRPC will be studied at the recommended Phase 2 dose (RP2D) determined in Part I over 12 weeks of daily dosing. Approximately 120 patients (40 in each cohort) will be enrolled.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: prostate cancer, clinical trial
This is a phase I, open-label trial to evaluate the safety and immunogenicity of INO 5150 alone or in combination with INO-9012 when delivered intramuscularly (IM) followed by electroporation (EP) in men with biochemically relapsed prostate cancer.
Wednesday, September 14, 2016 5:38 AM|Google News on 'cancer for a feed'|Labels: prostate cancer

Breakthrough in Prostrate Cancer research
Business Standard
When coupled with the milk protein lactoferrin, the Dox can be delivered directly into the nucleus of prostate cancer cells and will kill the cells as well as drug resistant cancer stem cells, without any side-effects. This has been published in the ...

and more »
Tuesday, September 13, 2016 11:38 PM|Quach Truong, Irene O. Justiniano, Aline L. Nocon, Julie T. Soon, Sandra Wissmueller, Douglas H. Campbell, Bradley J. Walsh|Journal of Cancer|Labels: prostate cancer, biomarker diagnostic

Prostate cancer is the most frequently diagnosed male visceral cancer and the second leading cause of cancer death in the United States. Standard tests such as prostate-specific antigen (PSA) measurement have poor specificity (33%) resulting in a high number of false positive reports. Consequently there is a need for new biomarkers to address this problem. The MIL-38 antibody was first described nearly thirty years ago, however, until now, the identification of the target antigen remained elusive. By a series of molecular techniques and mass spectrometry, the MIL-38 antigen was identified to be the highly glycosylated proteoglycan Glypican-1 (GPC-1). This protein is present in two forms; a membrane bound core protein of 55-60 kDa and secreted soluble forms of 40 kDa and 52 kDa. GPC-1 identification was confirmed by immuno-precipitation, western blots and ELISA. An ELISA platform is currently being developed to assess the levels of GPC-1 in normal, benign prostatic hyperplasia (BPH) and prostate cancer patients to determine whether secreted GPC-1 may represent a clinically relevant biomarker for prostate cancer diagnosis.

Tuesday, September 13, 2016 11:38 PM|Prosper Kanyong, Sean Rawlinson, James Davis|Journal of Cancer|Labels: prostate cancer, biomarker diagnostic

Prostate cancer (PCa) is a significant cause of morbidity and mortality and the most common cancer in men in Europe, North America, and some parts of Africa. The established methods for detecting PCa are normally based on tests using Prostate Specific Antigen (PSA) in blood, Prostate cancer antigen 3 (PCA3) in urine and tissue Alpha-methylacyl-CoA racemase (AMACR) as tumour markers in patient samples. Prior to the introduction of PSA in clinics, prostatic acid phosphatase (PAP) was the most widely used biomarker. An early diagnosis of PCa through the detection of these biomarkers requires the availability of simple, reliable, cost-effective and robust techniques. Immunoassays and nucleic acid detection techniques have experienced unprecedented growth in recent years and seem to be the most promising analytical tools. This growth has been driven in part by the surge in demand for near-patient-testing systems in clinical diagnosis. This article reviews immunochemical assays, and nucleic-acid detection techniques that have been used to clinically diagnose PCa.

Tuesday, September 13, 2016 11:38 PM|Zahraa I. Khamis, Kenneth A. Iczkowski, Yan-Gao Man, Mayassa J. Bou-Dargham, Qing-Xiang Amy Sang|Journal of Cancer|Labels: prostate cancer

Matrix metalloproteinases (MMPs) play intricate roles in cancer progression; some promote invasion and angiogenesis while others suppress tumor growth. For example, human MMP-26/endometase/matrilysin-2 was reported to be either protective or pro-tumorigenic. Our previous reports suggested pro-invasion and anti-inflammation properties in prostate cancer. Here, we provide evidence for a protective role of MMP-26 in the prostate. MMP-26 expression levels in androgen-repressed human prostate cancer (ARCaP) cells, transfected with sense or anti-sense MMP-26 cDNA, are directly correlated with those of the pro-apoptotic marker Bax. Immunohistochemical staining of prostate cancer tissue samples shows similar protein expression patterns, correlating the expression levels of MMP-26 and Bax in benign, neoplastic, and invasive prostate cancer tissues. The MMP-26 protein levels were upregulated in high grade prostate intraepithelial neoplasia (HGPIN) and decreased during the course of disease progression. Further analysis using an indirect terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay showed that many tumor cells expressing MMP-26 were undergoing apoptosis. This study showed that the high level of MMP-26 expression is positively correlated with the presence of apoptotic cells. This pro-apoptotic role of MMP-26 in human prostate cancer cells and tissues may enhance our understanding of the paradoxical roles of MMP-26 in tumor invasion and progression.

Tuesday, September 13, 2016 11:38 PM|Rie Amamoto, Takeshi Uchiumi, Mikako Yagi, Keisuke Monji, YooHyun Song, Yoshinao Oda, Masaki Shiota, Akira Yokomizo, Seiji Naito, Dongchon Kang|Journal of Cancer|Labels: electron transport, prostate cancer

Background: Mitochondria play crucial roles in cell signaling events, interorganellar communication, aging, cell proliferation and apoptosis, and mitochondrial impairment has been shown to accelerate or modulate cancer progression. Ubiquitous mitochondrial creatine kinase (uMtCK) is predominantly localized in the intermembrane space of mitochondria and catalyzes the reversible exchange of high-energy phosphate between adenosine tri-phosphate (ATP) and phosphocreatine. However, little is known about its expression and function in human prostate cancer progression.

Method: We investigated the expression of uMtCK in 148 prostate carcinoma tissues and matched normal tissue by immunohistochemistry. The expression and localization of uMtCK and hexokinase II, a marker of glycolysis, were examined in prostate carcinoma cell lines using western blot and immunofluorescence.

Results: MtCK expression was significantly lower in high Gleason grade carcinoma compared with normal prostate or low grade carcinoma. Western blot further revealed that uMtCK was highly expressed in LNCaP and 22Rv1 cell lines, as well as in the normal prostate cell line RWPE-1. However, uMtCK expression was almost absent in PC3 and DU145 cell lines, in correlation with absent or mutant p53 expression, respectively. In contrast, hexokinase II was overexpressed in PC3 cells. Moreover, in the low uMtCK expressing cell lines, glycolytic ATP production was increased, whereas mitochondrial ATP production was decreased.

Conclusions: These data suggest that uMtCK is downregulated as prostate cancer progresses in correlation with a metabolic switch in ATP usage.

Tuesday, September 13, 2016 10:05 PM|Vickman, R. E., Crist, S. A., Kerian, K., Eberlin, L., Cooks, R. G., Burcham, G. N., Buhman, K. K., Hu, C.-D., Mesecar, A. D., Cheng, L., Ratliff, T. L.|Molecular Cancer Research recent issues|Labels: AR, prostate cancer

Cholesterol accumulates in prostate lesions and has been linked to prostate cancer incidence and progression. However, how accumulated cholesterol contributes to prostate cancer development and progression is not completely understood. Cholesterol sulfate (CS), the primary sulfonation product of cholesterol sulfotransferase (SULT2B1b), accumulates in human prostate adenocarcinoma and precancerous prostatic intraepithelial neoplasia (PIN) lesions compared with normal regions of the same tissue sample. Given the enhanced accumulation of CS in these lesions, it was hypothesized that SULT2B1b-mediated production of CS provides a growth advantage to these cells. To address this, prostate cancer cells with RNAi-mediated knockdown (KD) of SULT2B1b were used to assess the impact on cell growth and survival. SULT2B1b is expressed and functional in a variety of prostate cells, and the data demonstrate that SULT2B1b KD, in LNCaP and other androgen-responsive (VCaP and C4-2) cells, results in decreased cell growth/viability and induces cell death. SULT2B1b KD also decreases androgen receptor (AR) activity and expression at mRNA and protein levels. While AR overexpression has no impact on SULT2B1b KD-mediated cell death, the addition of exogenous androgen is able to partially rescue the growth inhibition induced by SULT2B1b KD in LNCaP cells. These results suggest that SULT2B1b positively regulates the AR either through alterations in ligand availability or by interaction with critical coregulators that influence AR activity.

Implications: These findings provide evidence that SULT2B1b is a novel regulator of AR activity and cell growth in prostate cancer and should be further investigated for therapeutic potential. Mol Cancer Res; 14(9); 776–86. ©2016 AACR.

Tuesday, September 13, 2016 8:19 PM|Christopher J.D. Wallis, Aida Gordanpour, Jessica Stojcic Bendavid, Linda Sugar, Robert K. Nam, Arun Seth|Journal of Cancer (RSS 2.0)|Labels: prostate cancer

Background: MicroRNA (miRNA) have been shown to regulate gene expression in many cancers. MiR-182 has recently been found to be prognostic for patients treated with radical prostatectomy for prostate cancer. We sought to assess miR-182 as a prognostic marker and understand its role in prostate cancer progression and metastasis.

Methods: We analysed miR-182 expression among 147 men treated for prostate cancer using biochemical recurrence and metastasis as the endpoints. We examined miR-182 expression in prostate cancer cells and created cell lines that overexpressed miR-182 for functional assays. Finally, we examined pathways through which miR-182 may function using prediction algorithms and confirmed by Western blotting and knock-down assays.

Results: We found that miR-182 was not associated with biochemical recurrence (p=0.1111) or metastasis (p=0.9268) following radical prostatectomy. However, in mechanistic assays, we found that miR-182 expression was higher among aggressive prostate cancer cells and that ectopic miR-182 expression resulted in increased proliferation, migration and invasion in vitro. We identified FOXO1 as regulated by miR-182 in prostate cancer cells, confirmed that ectopic miR-182 expression resulted in diminished FOXO1 levels, and showed that miR-182 inhibition results in increased FOXO1 levels. Expression of FOXO1 (p=0.0014) in tumors from patients who developed biochemical recurrence compared to tumors from patients who were recurrence-free five years after their radical prostatectomy.

Conclusions: Our findings suggest that miR-182 may act to increase prostate cancer proliferation, migration and invasion through suppression of FOXO1. This may be valuable in the development of further therapeutic interventions.

Tuesday, September 13, 2016 8:19 PM|Mei Zhang, Xia Yuan, Bo Xu, Wei Guo, Fu-Xiang Ran, Run-Tao Li, Jing-Rong Cui|Journal of Cancer (RSS 2.0)|Labels: proteasome, prostate cancer, clinical trial

YSY01A is a new tripeptideboronic acid and an analog of PS341. However, YSY01A's antitumor effects and mechanism have not yet been elucidated. This study demonstrates that YSY01A inhibited proteasome activity by combining with the chymotrypsin-like (CT-L) site (β5i/β5), the post-glutamyl peptide hydrolase (PGPH) site (β1i/β1) and the trypsin-like (T-L) site (β2i/β2) in special fluorgonic substrates and proteasome probe tests. We explored the anticancer effect using methyl thiazolyltetrazolium (MTT) or sulforhodamine B (SRB), and PC-3M cells were sensitive to YSY01A among the four cancer cell types tested. The YSY01A antiproliferative effect was stronger than that of PS341. In vivo, YSY01A (1.25, 2.25, and 3.25 mg/kg) inhibited PC-3M cell xenograft tumor growth, and the tumor volume inhibition rate was approximately 40% to 60%. YSY01A arrested PC-3M cells in the G2/M phase of the cell cycle by flow cytometry (FCM). Many proteins related to the cell cycle were analyzed using western blot, and YSY01A was shown to increase p21, p27, cyclinB1, P-cdc2 (tyr15) and wee1 protein expression in both cells and tumor tissue in a concentration-dependent manner. YSY01A, a proteasome inhibitor, exerts anticancer effects on PC-3M cells in vitro and in vivo. The mechanism of the YSY01A-mediated antitumor effect is that the cell cycle is arrested at the G2/M stage. This study suggests that YSY01A may be a novel therapeutic agent for prostate cancer.

Tuesday, September 13, 2016 8:19 PM|Alexey Dubovenko, Tatiana Serebryiskaya, Yuri Nikolsky, Tatiana Nikolskaya, Ally Perlina, Lellean JeBailey, Svetlana Bureeva, Shilpa Katta, Shiv Srivastava, Albert Dobi, Tatiana Khasanova|Journal of Cancer (RSS 2.0)|Labels: prostate cancer

Background: Despite a growing number of studies evaluating cancer of prostate (CaP) specific gene alterations, oncogenic activation of the ETS Related Gene (ERG) by gene fusions remains the most validated cancer gene alteration in CaP. Prevalent gene fusions have been described between the ERG gene and promoter upstream sequences of androgen-inducible genes, predominantly TMPRSS2 (transmembrane protease serine 2). Despite the extensive evaluations of ERG genomic rearrangements, fusion transcripts and the ERG oncoprotein, the prognostic value of ERG remains to be better understood. Using gene expression dataset from matched prostate tumor and normal epithelial cells from an 80 GeneChip experiment examining 40 tumors and their matching normal pairs in 40 patients with known ERG status, we conducted a cancer signaling-focused functional analysis of prostatic carcinoma representing moderate and aggressive cancers stratified by ERG expression.

Results: In the present study of matched pairs of laser capture microdissected normal epithelial cells and well-to-moderately differentiated tumor epithelial cells with known ERG gene expression status from 20 patients with localized prostate cancer, we have discovered novel ERG associated biochemical networks.

Conclusions: Using causal network reconstruction methods, we have identified three major signaling pathways related to MAPK/PI3K cascade that may indeed contribute synergistically to the ERG dependent tumor development. Moreover, the key components of these pathways have potential as biomarkers and therapeutic target for ERG positive prostate tumors.

Tuesday, September 13, 2016 8:19 PM|Ferras Albitar, Kevin Diep, Wanlong Ma, Maher Albitar|Journal of Cancer (RSS 2.0)|Labels: prostate cancer

Background: Genomic association and linkage studies, as well as epidemiological data have implicated both the HOXB13 gene and single nucleotide polymorphisms (SNPs) in the development of prostate cancer (PCa). The recent association between the G84E polymorphism in the HOXB13 gene and PCa has been shown to result in a more aggressive cancer with an earlier onset of the disease. We examined the frequency of this mutation and other recurrent HOXB13 SNPs in patients with PCa and those with benign prostatic hyperplasia (BPH) or no cancer.

Methods: Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed on exons 1 and 2 of HOXB13 gene, followed by bidirectional Sanger Sequencing on peripheral blood from 232 PCa (age 46-92) and 110 BPH (age 45-84) patients. Statistical analysis was used to correlate between recurrent SNPs and PCa.

Results: The G84E mutation was found at a low frequency in randomly selected PCa and BPH (both 0.9%). Two recurrent, synonymous SNPs, rs8556 and rs900627, were also detected. rs8556 was detected in 48 PCa (20.7%) and 26 BPH (23.6%) subjects; rs9900627was detected in 27 PCa (11.6%) and 19 BPH (17.3%) subjects. Having both rs8556 and rs9900627 or being homozygous for either one was associated with being 2.9 times less likely to develop PCa (p=0.05).

Conclusions: Although a larger study in order to confirm our findings, our data suggests a significant negative correlation between two SNPs, rs8556 and rs9900627, and the presence of PCa.

Tuesday, September 13, 2016 8:19 PM|Beatriz A. Walter, Vladimir A. Valera, Peter A. Pinto, Maria J. Merino|Journal of Cancer|Labels: prostate cancer

MicroRNAs are small non-coding RNA molecules that have been shown to regulate the expression of genes linked to cancer. The relevance of microRNAs in the development, progression and prognosis of prostate cancer is not fully understood. It is also possible that these specific molecules may assist in the recognition of aggressive tumors and the development of new molecular targets. Our study investigated the importance of several microRNAs in cases of prostate cancer from 37 patients that were manually microdissected to obtain pure populations of tumor cells, normal epithelium and adjacent stroma. MicroRNA was extracted for PCR array profiling. Differentially expressed miRNAs for each case were used to compare tumor vs. normal epithelium and tumor-adjacent stroma samples.

Loss of 18 miRNAs (e.g.miR-34c, miR-29b, miR-212 and miR-10b) and upregulation of miR-143 and miR-146b were significantly found in all the tumors in comparison with normal epithelium and/or stroma (p≤ 0.001). A different signature was found in the high grade tumors (Gleason score ≥ 8) when compared with tumors Gleason score 6. Upregulation of miR-122, miR-335, miR-184, miR-193, miR-34, miR-138, miR-373, miR-9, miR-198, miR-144 and miR-215 and downregulation of miR-96, miR-222, miR-148, miR-92, miR-27, miR-125, miR-126, miR-27 were found in the high grade tumors.

MicroRNA profiling in prostate cancer appears to have unique expression patterns in comparison with normal tissue. These differential expressed miRNAs may provide novel diagnostic and prognostic tools that will assist in the recognition of prostate cancers with aggressive behavior.

Tuesday, September 13, 2016 4:20 PM|ClinicalKey Latest Issue: European Journal of Surgical Oncology|Labels: prostate cancer
European Journal of Surgical Oncology, Volume 42, Issue 9, 2016 Sep | Abou El-Kasem, F.; Abulkheir, I.; Sidhom, N.;...
Background/purpose : Prostate cancer is the second most common cancer in men worldwide. Many studies have focused on the significance of AMACR expression as a diagnostic marker for prostatic carcinoma. Similar studies relating immunohistochemical ...
Tuesday, September 13, 2016 2:05 PM|T.J. Wallace, T. Torre, M. Grob, J. Yu, I. Avital, BLDM Brücher, A. Stojadinovic, Y.G. Man|Journal of Cancer|Labels: prostate cancer

Prostate cancer is the most commonly diagnosed non-cutaneous neoplasm in men in the United States and the second leading cause of cancer mortality. One in 7 men will be diagnosed with prostate cancer during their lifetime. As a result, monitoring treatment response is of vital importance. The cornerstone of current approaches in monitoring treatment response remains the prostate-specific antigen (PSA). However, with the limitations of PSA come challenges in our ability to monitor treatment success. Defining PSA response is different depending on the individual treatment rendered potentially making it difficult for those not trained in urologic oncology to understand. Furthermore, standard treatment response criteria do not apply to prostate cancer further complicating the issue of treatment response. Historically, prostate cancer has been difficult to image and no single modality has been consistently relied upon to measure treatment response. However, with newer imaging modalities and advances in our understanding and utilization of specific biomarkers, the future for monitoring treatment response in prostate cancer looks bright.

Monday, September 12, 2016 6:00 PM|Donatella Tramontano|International Journal of Molecular Sciences|Labels: ROS, prostate cancer
Resveratrol, a dietary polyphenol, is under consideration as chemopreventive and chemotherapeutic agent for several diseases, including cancer. However, its mechanisms of action and its effects on non-tumor cells, fundamental to understand its real efficacy as chemopreventive agent, remain largely unknown. Proline-rich tyrosine kinase 2 (PYK2), a non-receptor tyrosine kinase acting as signaling mediator of different stimuli, behaves as tumor-suppressor in prostate. Since, PYK2 and RSV share several fields of interaction, including oxidative stress, we have investigated their functional relationship in human non-transformed prostate EPN cells and in their tumor-prone counterpart EPN-PKM, expressing a PYK2 dead-kinase mutant. We show that RSV has a strong biological activity in both cell lines, decreasing ROS production, inducing morphological changes and reversible growth arrest, and activating autophagy but not apoptosis. Interestingly, the PYK2 mutant increases basal ROS and autophagy levels, and modulates the intensity of RSV effects. In particular, the anti-oxidant effect of RSV is more potent in EPN than in EPN-PKM, whereas its anti-proliferative and pro-autophagic effects are more significant in EPN-PKM. Consistently, PYK2 depletion by RNAi replicates the effects of the PKM mutant. Taken together, our results reveal that PYK2 and RSV act on common cellular pathways and suggest that RSV effects on prostate cells may depend on mutational-state or expression levels of PYK2 that emerges as a possible mediator of RSV mechanisms of action. Moreover, the observation that resveratrol effects are reversible and not associated to apoptosis in tumor-prone EPN-PKM cells suggests caution for its use in humans.
Monday, September 12, 2016 1:00 AM|MIT Biotech Group - Essential Biotech RSS Feed|Labels: prostate cancer, financial
Immuno-oncology company Advantagene Inc. (Auburndale, Mass.) raised $14.2 million in a series A round from undisclosed investors. The National Securities Corp. subsidiary of National Holdings Corp. (NASDAQ:NHLD) was the placement agent.The funding is Advantagene's first significant outside investment since it was founded in 1999, CBO Stephen Rocamboli told BioCentury. Advantagene has subsisted primarily on NIH funding since its inception, Rocamboli said.The company's Gene Mediated Cytotoxic Immunotherapy platform is designed to generate an immune response that augments the efficacy of existing therapies. Its lead program is ProstAtak, a prostate cancer therapy that combines vector AdV-tk aglatimagene besadenovec and the generic drug valacyclovir. Rocamboli said the company aims to treat the disease before recurrence to reduce or delay the need for radical therapy and reduce the risk of disease progression after radical treatment.Rocamboli said Advantagene expects data by around 2020 from a Phase III study of ProstAtak in newly diagnosed localized prostate cancer patients undergoing radiation therapy, and in 1Q18 from a Phase IIb study of the therapy in patients under active surveillance.
Sunday, September 11, 2016 11:00 PM|Mannan Baig, Abdul; Khan, Naveed A.; Effendi, Vardah; Rana, Zohaib; Ahmad, H.R.; Abbas, Farhat|Anti-Cancer Drugs - Published Ahead-of-Print|Labels: prostate cancer
Recent reports on acetylcholine muscarinic receptor subtype 3 (CHRM3) have shown its growth-promoting role in prostate cancer. Additional studies report the proliferative effect of the cholinergic agonist carbachol on prostate cancer by its agonistic action on CHRM3. This study shows that the type 1 acetylcholine muscarinic receptor (CHRM1) contributes toward the proliferation and growth of prostate cancer. We used growth and cytotoxic assays, the prostate cancer microarray database and CHRM downstream pathways' homology of CHRM subtypes to uncover multiple signals leading to the growth of prostate cancer. Growth assays showed that pilocarpine stimulates the proliferation of prostate cancer. Moreover, it shows that carbachol exerts an additional agonistic action on nicotinic cholinergic receptor of prostate cancer cells that can be blocked by tubocurarine. With the use of selective CHRM1 antagonists such as pirenzepine and dicyclomine, a considerable inhibition of proliferation of prostate cancer cell lines was observed in dose ranging from 15-60 [micro]g/ml. The microarray database of prostate cancer shows a dominant expression of CHRM1 in prostate cancer compared with other cholinergic subtypes. The bioinformatics of prostate cancer and CHRM pathways show that the downstream signalling include PIP3-AKT-CaM-mediated growth in LNCaP and PC3 cells. Our study suggests that antagonism of CHRM1 may be a potential therapeutic target against prostate cancer. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.
Friday, September 9, 2016 4:13 AM|buyresearchchemicalss|EGFR Tyrosine Kinase Inhibitors Activate Autophagy|Labels: AR, DHFR, prostate cancer

Androgen Receptor (AR)-dependent transcription is a significant drivers of prostate tumor cell proliferation. in androgen-dependent prostate tumor cell lines. These outcomes claim that selective AR degradation could be an effective restorative prostate Ibuprofen Lysine (NeoProfen) tumor technique in the framework of AR mutations that confer level of resistance to third era AR antagonists. Ibuprofen Lysine (NeoProfen) DHFR by non-covalent appendage of the hydrophobic label[13]. An integral next thing in the advancement of the nascent technology can be to degrade medically relevant focus on proteins with a little drug-like molecule. To the end right here we display that coupling a hydrophobic label for an androgen receptor agonist changes it to a powerful Selective Androgen Receptor Degrader (SARD) with the capacity of inducing >50% of AR degradation (DC50) at 1 μM. Incredibly this SARD maintained anti-proliferative activity in cell lines resistant to current standard-of-care medicines for castration-resistant prostate tumor (CRPC). The androgen receptor (AR)[14] can be a ligand-dependent transcription element that upon binding towards the androgen dihydrotestosterone (DHT) goes through Ibuprofen Lysine (NeoProfen) a conformational modification resulting in homodimerization nuclear translocation and upregulation of gene transcription. While essential for the standard advancement and maintenance of the prostate AR-mediated gene manifestation remains a significant drivers throughout prostate tumor progression. Many restorative strategies concentrate on regulating AR activity. For instance Ibuprofen Lysine (NeoProfen) androgen deprivation therapy[15] coupled with AR antagonists (we.e. anti-androgens) such as for example bicalutamide[16] continues to be used like a first-line treatment for early stage prostate tumor for many years. While initially able to suppressing tumor development this strategy generally leads towards the progression of the AR-dependent however androgen independent type of the condition (i.e. CRPC)[17] which is in charge of almost all prostate tumor deaths. Furthermore in CRPC the first-generation anti-androgen medicines such as for example bicalutamide[19] and flutamide[18] may screen AR agonist activity. While the systems in charge of the development to CRPC aren’t completely known it is becoming clear an increased degree of AR proteins exists in nearly all CRPC which agents focusing Rabbit Polyclonal to Cytochrome P450 24A1. on androgen synthesis and/or AR signaling such as for example abiraterone and MDV3100/enzalutamide respectively demonstrate medical advantage to CRPC individuals[20-22]. Hypothesizing that improved AR amounts may drive the introduction of CRPC and taking into consideration Ibuprofen Lysine (NeoProfen) the medical success from the selective estrogen receptor degrader (SERD) fulvestrant[23] we wanted to induce AR degradation via our hydrophobic tagging strategy. To do this we designed some selective androgen receptor degraders (SARDs) predicated on the high affinity AR agonist RU59063[24] linked via a brief PEG linker for an adamantyl group (Shape 1A) a hydrophobic degron been shown to be effective inside our previous use Halotag fusion proteins. Shape 1 Shape 1. (A) Constructions of Selective Androgen Receptor Degraders (SARDs) predicated on the androgen receptor agonist RU59063. (B) Immunoblot analyses of LNCaP human being prostate tumor cells incubated with SARDS or mother or father ligand every day and night. Gratifyingly such heterodimeric substances retained the capability to bind right to the AR (Shape S1): competition radioligand binding assay using [3H]-R1881 demonstrated that appending from the adamantyl group to RU59063 decreased affinity for the AR around 37-fold regarding SARD279 and almost 300-fold for SARD033. Relative to their binding affinities the synthesized SARDs induced AR degradation at sub-micromolar concentrations. For instance SARD279 where the adamantyl moiety can be combined to RU59063 with a 8 atom ester linkage decreased AR proteins amounts by 50% at 1 μM (DC50) (Shape 1B) while no degradation was recognized in cells treated using the parental AR ligand. SARD033 having an adamantyl moiety attached with a much longer ether linkage induced AR degradation having a Ibuprofen Lysine (NeoProfen) ~2 μM DC50 worth (Shape 1B). SARD-mediated AR degradation needs direct discussion with AR since co-incubation using the competitive AR agonist RU59063 clogged the experience of SARD279 (not really shown). Focus on degradation from the SARDs is selective for the AR predictably; the glucocorticoid receptor (GR) another steroid receptor not really identified by the mother or father ligand RU59063 isn’t degraded in LNCaP cells under circumstances that bring about near-complete degradation from the androgen receptor.

Thursday, September 8, 2016 6:00 PM|Martin Boegemann|International Journal of Molecular Sciences|Labels: prostate cancer
The purpose of this study was to evaluate the prognostic ability of early changes of total prostate specific antigen (tPSA), free PSA (fPSA), [−2]proPSA and the Prostate Health Index (PHI) following initiation of Abiraterone-therapy in men with castration resistant prostate cancer (mCRPC). In 25 patients, PSA-subforms were analyzed before and at 8–12 weeks under therapy as prognosticators of progression-free-survival (PFS) and overall survival (OS). Comparing patients with a PFS &lt; vs. ≥12 months by using Mann–Whitney–Wilcoxon Tests, the relative-median-change of tPSA (−0.1% vs. −86.8%; p = 0.02), fPSA (12.1% vs. −55.3%; p = 0.03) and [−2]proPSA (8.1% vs. −59.3%; p = 0.05) differed significantly. For men with ≤ vs. &gt;15 months of OS there was a non-significant trend for a difference in the relative-median-change of fPSA (17.0% vs. −46.3%; p = 0.06). In Kaplan–Meier analyses, declining fPSA and [−2]proPSA were associated with a longer median PFS (13 months, 95% confidence interval (CI): 9.6–16.4 vs. 10 months, 95% CI: 3.5–16.5; p = 0.11), respectively. Correspondingly, decreasing fPSA and [−2]proPSA values indicated an OS of 32 months (95% CI: not reached (NR)) compared to 21 months in men with rising values (95% CI: 7.7–34.3; p = 0.14), respectively. We concluded that the addition of fPSA- and [−2]proPSA-changes to tPSA-information might be further studied as potential markers of early Abiraterone response in mCRPC patients.
Thursday, September 8, 2016 1:00 AM|MIT Biotech Group - Essential Biotech RSS Feed|Labels: prostate cancer, financial
Diagnostics company Armune Bioscience Inc. (Kalamazoo, Mich.) closed its series A round at $5 million with the addition of investments from Grand Angels Venture Fund and the University of Michigan's Michigan Investment in New Technology Start-ups (MINTS) program. In March, it had announced a $4 million first close without naming its investors.The company is retaining Mavericks Capital to raise a planned $25 million series B round.Armune markets APIFINY, a non-PSA blood test for prostate cancer, and intends to develop new tests for prostate, lung and breast cancers.
Tuesday, September 6, 2016 10:39 AM|Gupta, S., Li, J., Kemeny, G., Bitting, R. L., Beaver, J., Somarelli, J., Ware, K. E., Gregory, S., Armstrong, A. J.|Clinical Cancer Research Online First Articles|Labels: prostate cancer

Purpose: Beyond enumeration, circulating tumor cells (CTCs) can provide genetic information from metastatic cancer that may facilitate a greater understanding of tumor biology and enable a precision medicine approach. Experimental design: CTCs and paired leukocytes from men with metastatic castration-resistant prostate cancer (mCRPC) were isolated from blood through red cell lysis, CD45 depletion, and flow sorting based on EpCAM/CD45 expression. We next performed whole genomic copy number analysis of CTCs and matched patient leukocytes (germline) using array-based comparative genomic hybridization (aCGH) from 16 men with mCRPC, including longitudinal and sequential CTCs aCGH analyses in the context of enzalutamide therapy. Results: All patients had mCRPC and primary or acquired resistance to abiraterone acetate or enzalutamide. We compiled copy gains and losses, with a particular focus on those genes highly implicated in mCRPC progression and previously validated as being aberrant in metastatic tissue samples and genomic studies of reference mCRPC datasets. Genomic gains in >25% of CTCs were observed in AR, FOXA1, ABL1, MET, ERG, CDK12, BRD4, and ZFHX3, while common genomic losses involved PTEN, ZFHX3, PDE4DIP, RAF1, and GATA2. Analysis of aCGH in a sample with sequential enzalutamide resistant visceral progression showed acquired loss of AR amplification concurrent with gain of MYCN, consistent with evolution toward a neuroendocrine-like, AR-independent clone. Conclusions: Genomic analysis of pooled CTCs in men with mCRPC suggests a reproducible, but highly complex molecular profile that includes common aberrations in AR, ERG, c-MET, and PI3K signaling during mCRPC progression, which may be useful for predictive biomarker development.

Tuesday, September 6, 2016 9:36 AM|Alhasan, A. H., Scott, A. W., Wu, J. J., Feng, G., Meeks, J. J., Thaxton, C. S., Mirkin, C. A.|PNAS - RSS feed of Early Edition articles|Labels: prostate cancer, biomarker diagnostic
We report the identification of a molecular signature using the Scano-miR profiling platform based on the differential expression of circulating microRNAs (miRNA, miR) in serum samples specific to patients with very high-risk (VHR) prostate cancer (PCa). Five miRNA PCa biomarkers (miR-200c, miR-605, miR-135a*, miR-433, and miR-106a) were identified as useful...
Monday, September 5, 2016 6:00 PM|Farshid Dayyani, Amado J. Zurita, Graciela M. Nogueras-González, Rebecca Slack, Randall E. Millikan, John C. Araujo, Gary E. Gallick, Christopher J. Logothetis and Paul G. Corn|Articles: MD Anderson Cancer Center|Labels: prostate cancer
We hypothesized that pretreatment serum levels of insulin and other serum markers would predict Progression-free survival (PFS), defined as time to castration-resistant progression or death, in metastatic andr...
Thursday, September 1, 2016 10:05 PM|Hernandez-Hoyos, G., Sewell, T., Bader, R., Bannink, J., Chenault, R. A., Daugherty, M., Dasovich, M., Fang, H., Gottschalk, R., Kumer, J., Miller, R. E., Ravikumar, P., Wiens, J., Algate, P. A., Bienvenue, D., McMahan, C. J., Natarajan, S. K., Gross, J. A., Blankenship, J. W.|Molecular Cancer Therapeutics current issue|Labels: prostate cancer

Treatment of metastatic, castration-resistant prostate cancer (mCRPC) remains a highly unmet medical need and current therapies ultimately result in disease progression. Immunotherapy is a rapidly growing approach for treatment of cancer but has shown limited success to date in the treatment of mCRPC. We have developed a novel humanized bispecific antibody, MOR209/ES414, built on the ADAPTIR (modular protein technology) platform, to redirect T-cell cytotoxicity toward prostate cancer cells by specifically targeting T cells through CD3 to prostate cancer cells expressing PSMA (prostate-specific membrane antigen). In vitro cross-linking of T cells with PSMA-expressing tumor cells by MOR209/ES414 triggered potent target-dependent tumor lysis and induction of target-dependent T-cell activation and proliferation. This activity occurred at low picomolar concentrations of MOR209/ES414 and was effective at low T-effector to tumor target cell ratios. In addition, cytotoxic activity was equivalent over a wide range of PSMA expression on target cells, suggesting that as few as 3,700 PSMA receptors per cell are sufficient for tumor lysis. In addition to high sensitivity and in vitro activity, MOR209/ES414 induced limited production of cytokines compared with other bispecific antibody formats. Pharmacokinetic analysis of MOR209/ES414 demonstrated a serum elimination half-life in NOD/SCID (NSG) mice of 4 days. Administration of MOR209/ES414 in murine xenograft models of human prostate cancer significantly inhibited tumor growth, prolonged survival, and decreased serum prostate-specific antigen levels only in the presence of adoptively transferred human T cells. On the basis of these preclinical findings, MOR209/ES414 warrants further investigation as a potential therapeutic for the treatment of CRPC. Mol Cancer Ther; 15(9); 2155–65. ©2016 AACR.

Wednesday, August 31, 2016 10:05 PM|D. G.|JournalTOCs API - Clinical Cancer Research (27 articles)|Labels: prostate cancer

Defining Castration-Resistant Prostate Cancer Stem Cells
Chen, X Li, Q, Liu, X, Liu, C, Liu, R, Rycaj, K, Zhang, D, Liu, B, Jeter, C, Calhoun-Davis, T, Lin, K, Lu, Y, Chao, H.-P, Shen, J, Tang, D. G.
Clinical Cancer Research, Vol. 22, No. 17 (2016) pp. 4505 - 4516
Purpose: We have shown that the phenotypically undifferentiated (PSA&ndash;/lo) prostate cancer cell population harbors long-term self-renewing cancer stem cells (CSC) that resist castration, and a subset of the cells within the PSA&ndash;/lo population bearing the ALDHhiCD44+&alpha;2&beta;1+ phenotype (Triple Marker+/TM+) is capable of robustly initiating xenograft tumors in castrated mice. The goal of the current project is to further characterize the biologic properties of TM+ prostate cancer cell population, particularly in the context of initiating and propagating castration-resistant prostate cancer (CRPC). Experimental Design: The in vivo CSC activities were measured by limiting-dilution serial tumor transplantation assays in both androgen-dependent and androgen-independent prostate cancer xenograft models. In vitro clonal, clonogenic, and sphere-formation assays were conducted in cells purified from xenograft and patient tumors. qPCR, Western blot, lentiviral-mediated gene knockdown, and human microRNA arrays were performed for mechanistic studies. Results: By focusing on the LAPC9 model, we show that the TM+ cells are CSCs with both tumor-initiating and tumor-propagating abilities for CRPC. Moreover, primary patient samples have TM+ cells, which possess CSC activities in "castrated" culture conditions. Mechanistically, we find that (i) the phenotypic markers are causally involved in CRPC development; (ii) the TM+ cells preferentially express castration resistance and stem cell&ndash;associated molecules that regulate their CSC characteristics; and (iii) the TM+ cells possess distinct microRNA expression profiles and miR-499-5p functions as an oncomir. Conclusions: Our results define the TM+ prostate cancer cells as a population of preexistent stem-like cancer cells that can both mediate and propagate CRPC and highlight the TM+ cell population as a therapeutic target. Clin Cancer Res; 22(17); 4505&ndash;16. &copy;2016 AACR.

Wednesday, August 31, 2016 10:05 PM|M. D.|JournalTOCs API - Clinical Cancer Research (27 articles)|Labels: prostate cancer

EPI Overcomes Resistance Mechanisms in CRPC
Yang, Y. C Banuelos, C. A, Mawji, N. R, Wang, J, Kato, M, Haile, S, McEwan, I. J, Plymate, S, Sadar, M. D.
Clinical Cancer Research, Vol. 22, No. 17 (2016) pp. 4466 - 4477
Purpose: Persistent androgen receptor (AR) transcriptional activity is clinically evident in castration-resistant prostate cancer (CRPC). Therefore, AR remains as a viable therapeutic target for CRPC. All current hormonal therapies target the C-terminus ligand-binding domain (LBD) of AR. By using EPI to target AR activation function-1 (AF-1), in the N-terminal domain that is essential for AR transactivation, we evaluate the ability of EPI to overcome several clinically relevant AR-related mechanisms of resistance. Experimental Design: To study the effect of EPI on AR transcriptional activity against overexpressed coactivators, such as SRC1-3 and p300, luciferase reporter assays were performed using LNCaP cells. AR-negative COS-1 cells were employed for reporter assays to examine whether the length of polyglutamine tract affects inhibition by EPI. The effect of EPI on constitutively active AR splice variants was studied in LNCaP95 cells, which express AR-V7 variant. To evaluate the effect of EPI on the proliferation of LNCaP95 cells, we performed in vitro BrdUrd incorporation assay and in vivo studies using xenografts in mice. Results: EPI effectively overcame several molecular alterations underlying aberrant AR activity, including overexpressed coactivators, AR gain-of-function mutations, and constitutively active AR-V7. EPI inhibited AR transcriptional activity regardless of the length of polyglutamine tract. Importantly, EPI significantly inhibited the in vitro and in vivo proliferation of LNCaP95 prostate cancer cells, which are androgen independent and enzalutamide resistant. Conclusions: These findings support EPI as a promising therapeutic agent to treat CRPC, particularly against tumors driven by constitutively active AR splice variants that are resistant to LBD-targeting drugs. Clin Cancer Res; 22(17); 4466&ndash;77. &copy;2016 AACR. See related commentary by Sharp et al., p. 4280

Wednesday, August 31, 2016 10:05 PM|You, S., Knudsen, B. S., Erho, N., Alshalalfa, M., Takhar, M., Al-deen Ashab, H., Davicioni, E., Karnes, R. J., Klein, E. A., Den, R. B., Ross, A. E., Schaeffer, E. M., Garraway, I. P., Kim, J., Freeman, M. R.|Cancer Research recent issues|Labels: prostate cancer
Prostate cancer is a biologically heterogeneous disease with variable molecular alterations underlying cancer initiation and progression. Despite recent advances in understanding prostate cancer heterogeneity, better methods for classification of prostate cancer are still needed to improve prognostic accuracy and therapeutic outcomes. In this study, we computationally assembled a large virtual cohort (n = 1,321) of human prostate cancer transcriptome profiles from 38 distinct cohorts and, using pathway activation signatures of known relevance to prostate cancer, developed a novel classification system consisting of three distinct subtypes (named PCS1–3). We validated this subtyping scheme in 10 independent patient cohorts and 19 laboratory models of prostate cancer, including cell lines and genetically engineered mouse models. Analysis of subtype-specific gene expression patterns in independent datasets derived from luminal and basal cell models provides evidence that PCS1 and PCS2 tumors reflect luminal subtypes, while PCS3 represents a basal subtype. We show that PCS1 tumors progress more rapidly to metastatic disease in comparison with PCS2 or PCS3, including PSC1 tumors of low Gleason grade. To apply this finding clinically, we developed a 37-gene panel that accurately assigns individual tumors to one of the three PCS subtypes. This panel was also applied to circulating tumor cells (CTC) and provided evidence that PCS1 CTCs may reflect enzalutamide resistance. In summary, PCS subtyping may improve accuracy in predicting the likelihood of clinical progression and permit treatment stratification at early and late disease stages. Cancer Res; 76(17); 4948–58. ©2016 AACR.
Wednesday, August 31, 2016 10:05 PM|Wang, Y., Dehigaspitiya, D. C., Levine, P. M., Profit, A. A., Haugbro, M., Imberg-Kazdan, K., Logan, S. K., Kirshenbaum, K., Garabedian, M. J.|Cancer Research recent issues|Labels: prostate cancer
Development of resistance to antiandrogens for treating advanced prostate cancer is a growing concern and extends to recently developed therapeutics, including enzalutamide. Therefore, new strategies to block androgen receptor (AR) function in prostate cancer are required. Here, we report the characterization of a multivalent conjugate presenting two bioactive ethisterone ligands arrayed as spatially defined pendant groups on a peptoid oligomer. The conjugate, named Multivalent Peptoid Conjugate 6 (MPC6), suppressed the proliferation of multiple AR-expressing prostate cancer cell lines including those that failed to respond to enzalutamide and ARN509. The structure–activity relationships of MPC6 variants were evaluated, revealing that increased spacing between ethisterone moieties and changes in peptoid topology eliminated its antiproliferative effect, suggesting that both ethisterone ligand presentation and scaffold characteristics contribute to MPC6 activity. Mechanistically, MPC6 blocked AR coactivator–peptide interaction and prevented AR intermolecular interactions. Protease sensitivity assays suggested that the MPC6-bound AR induced a receptor conformation distinct from that of dihydrotestosterone- or enzalutamide-bound AR. Pharmacologic studies revealed that MPC6 was metabolically stable and displayed a low plasma clearance rate. Notably, MPC6 treatment reduced tumor growth and decreased Ki67 and AR expression in mouse xenograft models of enzalutamide-resistant LNCaP-abl cells. Thus, MPC6 represents a new class of compounds with the potential to combat treatment-resistant prostate cancer. Cancer Res; 76(17); 5124–32. ©2016 AACR.
Wednesday, August 31, 2016 10:05 PM|Unknown Author|Cancer Discovery current issue|Labels: prostate cancer

A new study finds that 11.8% of men with metastatic prostate cancer carry mutations in DNA repair genes. The mutations were more than five times as prevalent in men with metastatic disease as in men with localized prostate cancer. Although relatives of the men weren't more likely to have prostate cancer, they were more likely to have breast, ovarian, and other cancers.

Friday, August 26, 2016 1:20 PM|Elsevier|JournalTOCs API - Biochemical and Biophysical Research Communications (50 articles)|Labels: prostate cancer

Downregulation of miR-17-92a cluster promotes autophagy induction in response to celastrol treatment in prostate cancer cells

Biochemical and Biophysical Research Communications, Vol. , No. (2016) pp. -
Publication date: 16 September 2016 Source:Biochemical and Biophysical Research Communications, Volume 478, Issue 2 Author(s): Jianquan Guo, Yu Mei, Kai Li, Xuemei Huang, Huanjie Yang Celastrol has potential application for the treatment of prostate cancer. However it causes autophagy as a protective response in prostate and other types of cancers, thus unveiling the underlying mechanisms may benefit its future application. In the present study, we demonstrate that the miR-17-92a cluster plays a negative role in celastrol induced-autophagy. Dissection of miR-17-92a cluster revealed the role of miR-17 seed family (miR-20a and miR-17) in autophagy inhibition in the context of prostate cancer cells. Autophagy-related gene ATG7 was validated as a target of miR-17 seed family by dual-luciferase assay and qPCR. Celastrol induced autophagy was inhibited by miR-20a or miR-17, while the inhibitory effects were rescued in the presence of pcDNA-ATG7 lacking 3′ UTR, demonstrating that these two members target ATG7 to inhibit celastrol-induced autophagy. As celastrol degrades androgen receptor (AR), a key transcription factor in prostate cancer cells, we further investigated whether AR affected miR-17-92a expression in prostate cancer cells. AR binding sites were found in the promoter and two introns of miR-17-92a. In addition, higher expression levels of miR-17-92a were observed in AR positive cells compared with AR negative cells. Ectopic expression of AR could enhance the expression of miR-17-92a cluster in AR-negative prostate cancer cells while knockdown of AR decreased miR-17-92a expression in AR-positive cells, demonstrating the regulation of AR on miR-17-92a transcription. In summary, our results demonstrate that celastrol downregulates AR and its target miR-17-92a, leading to autophagy induction in prostate cancer cells.

Tuesday, August 23, 2016 6:00 PM|Axel Thomson|Cancers|Labels: HSP, prostate cancer
Background: Prostate cancer-associated fibroblasts (CAF) can stimulate malignant progression and invasion of prostatic tumour cells via several mechanisms including those active in extracellular matrix; Methods: We isolated CAF from prostate cancer patients of Gleason Score 6–10 and confirmed their cancer-promoting activity using an in vivo tumour reconstitution assay comprised of CAF and BPH1 cells. We tested the effects of heat shock protein 90 (HSP90) inhibitors upon reconstituted tumour growth in vivo. Additionally, CAF contractility was measured in a 3D collagen contraction assay and migration was measured by scratch assay; Results: HSP90 inhibitors dipalmitoyl-radicicol and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) reduced tumour size and proliferation in CAF/BPH1 reconstituted tumours in vivo. We observed that the most contractile CAF were derived from patients with lower Gleason Score and of younger age compared with the least contractile CAF. HSP90 inhibitors radicicol and 17-DMAG inhibited contractility and reduced the migration of CAF in scratch assays. Intracellular levels of HSP70 and HSP90 were upregulated upon treatment with HSP90 inhibitors. Inhibition of HSP90 also led to a specific increase in transforming growth factor beta 2 (TGFβ2) levels in CAF; Conclusions: We suggest that HSP90 inhibitors act not only upon tumour cells, but also on CAF in the tumour microenvironment.
Tuesday, August 23, 2016 7:46 AM|Google News on 'breast cancer'|Labels: BRCA, prostate cancer

Health Essentials from Cleveland Clinic (blog)

Why Would Men Need Genetic Testing for Breast Cancer Too?
Health Essentials from Cleveland Clinic (blog)
Men can carry BRCA1/2 mutations too, and they increase a man's risk for developing prostate cancer, melanoma, pancreatic and testicular cancer — as well as ...

and more »
Monday, August 22, 2016 8:40 AM|Sharp, A., Welti, J., Blagg, J., de Bono, J. S.|Clinical Cancer Research Online First Articles|Labels: AR, prostate cancer

Androgen receptor (AR) splice variants (SV) have been implicated in the development of metastatic castration-resistant prostate cancer and resistance to AR targeting therapies, including abiraterone and enzalutamide. Agents targeting AR-SV are urgently needed to test this hypothesis and further improve the outcome of patients suffering from this lethal disease. Clin Cancer Res; 22(17); 1–3. ©2016 AACR.

See related article by Yang et al., p. 4466

Monday, August 22, 2016 8:40 AM|Yang, Y. C., Banuelos, C. A., Mawji, N. R., Wang, J., Kato, M., Haile, S., McEwan, I. J., Plymate, S., Sadar, M. D.|Clinical Cancer Research Online First Articles|Labels: AR, prostate cancer

Purpose: Persistent androgen receptor (AR) transcriptional activity is clinically evident in castration-resistant prostate cancer (CRPC). Therefore, AR remains as a viable therapeutic target for CRPC. All current hormonal therapies target the C-terminus ligand-binding domain (LBD) of AR. By using EPI to target AR activation function-1 (AF-1), in the N-terminal domain that is essential for AR transactivation, we evaluate the ability of EPI to overcome several clinically relevant AR-related mechanisms of resistance.

Experimental Design: To study the effect of EPI on AR transcriptional activity against overexpressed coactivators, such as SRC1-3 and p300, luciferase reporter assays were performed using LNCaP cells. AR-negative COS-1 cells were employed for reporter assays to examine whether the length of polyglutamine tract affects inhibition by EPI. The effect of EPI on constitutively active AR splice variants was studied in LNCaP95 cells, which express AR-V7 variant. To evaluate the effect of EPI on the proliferation of LNCaP95 cells, we performed in vitro BrdUrd incorporation assay and in vivo studies using xenografts in mice.

Results: EPI effectively overcame several molecular alterations underlying aberrant AR activity, including overexpressed coactivators, AR gain-of-function mutations, and constitutively active AR-V7. EPI inhibited AR transcriptional activity regardless of the length of polyglutamine tract. Importantly, EPI significantly inhibited the in vitro and in vivo proliferation of LNCaP95 prostate cancer cells, which are androgen independent and enzalutamide resistant.

Conclusions: These findings support EPI as a promising therapeutic agent to treat CRPC, particularly against tumors driven by constitutively active AR splice variants that are resistant to LBD-targeting drugs. Clin Cancer Res; 22(17); 1–12. ©2016 AACR.

See related commentary by Sharp et al., p. 4280

Monday, August 22, 2016 6:06 AM|Google News on 'cancer for a feed'|Labels: prostate cancer, financial

Reuters Blogs

Pfizer spends $14B on Medivation in cancer fight
Colorado Springs Gazette
The New York drugmaker said Monday that the acquisition will stock its product portfolio with leading treatments for the most common cancers in men and women by adding Medivation's pricey prostate cancer treatment Xtandi to a lineup that already ...
Pfizer To Acquire Medivation | Pfizer: One of the world's premier biopharmaceutical companiesPfizer

all 436 news articles »
Wednesday, August 17, 2016 6:00 PM|Veda N. Giri, Jennifer Beebe-Dimmer|Seminars in Oncology|Labels: prostate cancer
Prostate cancer is the most commonly diagnosed cancer among men in the United States as well as most Western countries. A significant proportion of men report having a positive family history of prostate cancer in a first-degree relative (father, brother, son), which is important in that family history is one of the only established risk factors for the disease and plays a role in decision-making for prostate cancer screening. Familial aggregation of prostate cancer is considered a surrogate marker of genetic susceptibility to developing the disease, but shared environment cannot be excluded as an explanation for clustering of cases among family members.
Tuesday, August 16, 2016 10:39 AM|Kockan, C., Hach, F., Sarrafi, I., Bell, R. H., McConeghy, B., Beja, K., Haegert, A., Wyatt, A. W., Volik, S. V., Chi, K. N., Collins, C. C., Sahinalp, S. C.|Bioinformatics - Advance Access|Labels: prostate cancer

Motivation: Successful development and application of precision oncology approaches require robust elucidation of the genomic landscape of a patient’s cancer and, ideally, the ability to monitor therapy-induced genomic changes in the tumour in an inexpensive and minimally invasive manner. Thanks to recent advances in sequencing technologies, "liquid biopsy", the sampling of patient’s bodily fluids such as blood and urine, is considered as one of the most promising approaches to achieve this goal. In many cancer patients, and especially those with advanced metastatic disease, deep sequencing of circulating cell-free DNA (cfDNA) obtained from patient’s blood yields a mixture of reads originating from the normal DNA and from multiple tumour subclones - called circulating tumour DNA or ctDNA. The ctDNA/cfDNA ratio as well as the proportion of ctDNA originating from specific tumour subclones depend on multiple factors, making comprehensive detection of mutations difficult, especially at early stages of cancer. Furthermore, sensitive and accurate detection of SNVs and indels from cfDNA is constrained by several factors such as the sequencing errors and PCR artifacts, and mapping errors related to repeat regions within the genome. In this paper, we introduce SiNVICT, a computational method that increases the sensitivity and specificity of SNV and indel detection at very low variant allele frequencies. SiNVICT has the capability to handle multiple sequencing platforms with different error properties; it minimises false positives resulting from mapping errors and other technology specific artifacts including strand bias and low base quality at read ends. SiNVICT also has the capability to perform time-series analysis, where samples from a patient sequenced at multiple time points are jointly examined to report locations of interest where there is a possibility that certain clones were wiped out by some treatment while some subclones gained selective advantage.

Results: We tested SiNVICT on simulated data as well as prostate cancer cell lines and cfDNA obtained from castration-resistant prostate cancer patients. On both simulated and biological data, SiNVICT was able to detect SNVs and indels with variant allele percentages as low as 0.5%. The lowest amounts of total DNA used for the biological data where SNVs and indels could be detected with very high sensitivity were 2.5ng on the Ion Torrent platform and 10ng on Illumina. With increased sequencing and mapping accuracy, SiNVICT might be utilised in clinical settings, making it possible to track the progress of point mutations and indels that are associated with resistance to cancer therapies and provide patients personalised treatment. We also compared SiNVICT with other popular SNV callers such as MuTect, VarScan2, and Freebayes. Our results show that SiNVICT performs better than these tools in most cases and allows further data exploration such as time-series analysis on cfDNA sequencing data.

Availability: SiNVICT is available at:


Tuesday, August 16, 2016 12:33 AM|News from Mayo Clinic|Labels: prostate cancer
Prostate cancer treatment decisions If the first therapy to treat prostate cancer doesn't work, there are other options available — with one exception. Having all the information is a blessing and a curse According to Lonnie Fynskov, a Mayo Clinic nurse and patient educator, being a cancer nurse is helpful in understanding what’s happening when [...]
Sunday, August 14, 2016 10:05 PM|Shafi, A., Schiewer, M., Leeuw, R. d., McCue, P., Birbe, R., Gomella, L., Lallas, C., Trabulsi, E., Raj, G., Knudsen, K.|Clinical Cancer Research recent issues|Labels: prostate cancer

Prostate cancer (PCa) is the most common non-cutanenous cancer and the second leading cause of cancer-related death in American men. Androgen receptor (AR) is a hormone-activated transcription factor that plays an important role in both the development and progression of PCa. Androgen deprivation therapy is a common first-line therapy. However, many patients become resistant to such therapy and the tumor recurs. Thus, there is a vital need for the development of novel, more effective drugs. One major hurdle in this aspect is the lack of adequate preclinical models. Current models do not effectively recapitulate the heterogeneity and the microenvironment of human PCa tumors hindering the ability to accurately predict therapeutic response. Our lab has generated a method to culture patient tumors ex vivo termed patient derived explant (PDeX). This approach maintains the integrity of the native tumor microenvironment, tumor tissue morphology, and molecular signaling. Intriguingly, our PDEX model can be targeted with various therapeutic agents or lentiviral-based shRNAs to determine specific responses on individual tumor growth. Furthermore, with this model we can quantitatively assess drug efficacy on numerous parameters (i.e. AR levels, Ki67 staining, apoptosis screening). Data to be discussed will assess the variances in response to AR-directed therapeutics and underlying mechanisms of action. In addition, we can potentially identify clinically relevant subpopulations of patients and molecularly profile their cultured tissue to uncover new pathways for therapeutic intervention. Thus, the PDeX model allows for a comprehensive evaluation of individual tumors in their native microenvironment to ultimately develop more effective therapies.

Citation Format: Ayesha Shafi, Matthew Schiewer, Renee de Leeuw, Peter McCue, Ruth Birbe, Leonard Gomella, Costas Lallas, Edouard Trabulsi, Ganesh Raj, Karen Knudsen. Developing PDeX (Patient Derived Explant) to determine the basis for response to AR-directed therapeutics. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A12.

Sunday, August 14, 2016 10:05 PM|Xie, F., Kohli, M., Ping, Y., Jimenez, R. E., Weinshilboum, R. M., Wang, L.|Clinical Cancer Research recent issues|Labels: prostate cancer

Castration resistant prostate cancer (CRPC) is a deadly disease with a poor prognosis. Treatment options for CRPC patients involve taxanes or newly developed drugs targeting the androgen pathway or androgen synthesis, including CYP17 inhibitors. However, response to therapy varies dramatically among patients, which might be due, in part, to tumor heterogeneity. Therefore, understanding of the genomic landscape of CRPC would be important to help achieve better outcomes by developing personalized therapies. One challenge contributing to our lack of therapies for CRPC is a paucity of clinically relevant animal models predictive of response to therapy in human patients. The Prostate Cancer Medically Optimized Genome Enhanced Therapy (PROMOTE) study is a Mayo Clinic prospective trial designed for patients with metastatic CRPC who are treated with abiraterone acetate, a CYP17 inhibitor, over a 12 week period. Fresh tissue from metastatic lesions, primarily bone metastases, was obtained by needle core biopsy before and 12 weeks after initiating abiraterone acetate treatment. The samples were submitted for DNA and RNA sequencing and were also used to generate patient-derived xenograft (PDX) models. PDX models were developed by injecting biopsy samples subcutaneously or under the renal capsule in male non-obese diabetic (NOD)/severe combined immunodeficient (SCID) or NOD/SCID/IL-2-receptor null (NSG) mice implanted with 25mg testosterone pellets at the time of tissue implantation and 2 months later. Baseline samples from 103 unique patients as well as second samples from 61 patients post abiraterone acetate treatment were injected into approximately 600 mice. Of the samples for which pathology is currently available, 31% of the biopsies injected into mice were confirmed to include tumor tissue, which may be compared with a figure of 37.5% of samples sent for sequencing. Thus far, we have established 8 PDX models, four from baseline and four from post treatment samples. Seven models were derived from metastatic bone lesions, and one model from a liver metastasis. The tumor tissue in each model was expanded into a second of generation of mice and harvested when the tumors grew. No tumor was expanded more than four times. Genomic and transcriptomic analysis of xenograft tissue from different "generations" of xenograft expansion is ongoing and will be compared with similar data for the original biopsy. The evaluation of treatment response after exposure of these PDX models to different therapies including CYP19 inhibitors, AR blockers and taxanes is ongoing. These PDX models provide a tool for future drug testing and for studying mechanisms of resistance to therapy in CRPC.

Citation Format: Fang Xie, Manish Kohli, Yin Ping, Rafael E. Jimenez, Richard M. Weinshilboum, Liewei Wang. Developing patient derived xenograft (PDX) models for metastatic castration resistant prostate cancer (CRPC) during CYP17 inhibitor therapy. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A05.

Sunday, August 14, 2016 10:05 PM|Palanisamy, N., Yang, J., Wan, X., Tapia, E. M. l. N., Araujo, J. C., Efstathiou, E., Labanca, E., Pisters, L., Aparicio, A., Bhalla, R., Tomlins, S., Kunju, L. P., Chinnaiyan, A., Logothetis, C. J., Troncoso, P., Navone, N. M.|Clinical Cancer Research recent issues|Labels: prostate cancer

Patients with metastatic prostate cancer (PCa) have effective therapy options, but none of them are curative. Thus, their mortality rates are persistently high. Essential to furthering our progress in PCa research and therapy development is a spectrum of models that reflect the heterogeneity of the disease at each tumor site as well as the different histological variants of PCa (e.g., adenocarcinoma, small cell carcinoma). To address this challenge, we developed a strategy to establish PCa patient-derived xenografts (PDXs), using PCa tissue specimens taken from PCa sites demonstrating clinical progression. This approach provided a diverse repository of PDXs that can be linked prospectively with clinical progression and led to the identification of clinically relevant therapy targets and have proven valuable for testing drugs. We studied the first 50 PDXs developed under our program to a) define the histopathological features of paired human PCa and corresponding PDXs applying the clinically defined morphological characterization groupings of human cancer to the PDX tumors; b) assess the expression of genes known to play roles in PCa pathogenesis (e.g., androgen receptor, PTEN, ETS gene fusions) in PDXs and the human tumors of origin using immunohistochemistry and fluorescence in situ hybridization and c) perform array comparative genomic hybridization to 42 PDXs. We found that the histopathological and molecular pattern of these PDXs maintain the fidelity with the human tumor of origin. Furthermore, of the 50 cases studied, 32 (64%) were adenocarcinomas, and 16 (32%) were small cell carcinomas, poorly differentiated neuroendocrine carcinomas or mixed adenocarcinoma/ small cell carcinomas. In our cohort, we also have one sarcomatoid tumor and one ductal adenocarcinoma. Of the 32 adenocarcinomas in this cohort, 26 were AR-positive (81%), and 11 of the 27 AR-positive adenocarcinomas (41%) had aberrant expression of genes frequently involved in recurrent rearrangement (e.g., ERG, ETV1, ETV5). Also, SCCs and poorly differentiated neuroendocrine carcinomas did not express AR and were negative for ERG. This distribution recapitulates that of human PCa in the general population. Comparative genomic hybridization demonstrated gains and losses previously reported in PCa with a defined cluster of genomic aberrations. Significant differences in oncogenic pathways activation in pairs of PDXs derived from different areas of the same tumor suggesting divergent cellular progression. Finally, using this platform, we identified a focal deletion of speckle-type POZ protein-like (SPOPL) gene in 7/28 PDX. SPOPL is a MATH-BTB protein that shares an overall 85% sequence identity with SPOP (a SPOPL paralog). SPOP was recently reported to be mutated in about 8% of PCa and to define a molecular subclass of PCa. No mutations were found in SPOP in our cohort. In support of our findings, deletions on SPOPL were also found in about 7% of the PCa in TCGA data suggesting that our cohort is a reliable platform for discovery. In conclusion, we have developed a dynamic repository of clinically annotated samples that can be used as a discovery platform. Furthermore, these clinically annotated samples can be linked prospectively to clinical progression/response to therapy and thus will help define therapeutic targets for subpopulations of men and to identify likely responders to previous and upcoming therapies.

Citation Format: Nallasivam Palanisamy, Jun Yang, Xinhai Wan, Elsa M. li Ning Tapia, John C. Araujo, Eleni Efstathiou, Estefania Labanca, Louis Pisters, Ana Aparicio, Ritu Bhalla, Scott Tomlins, Lakshmi P. Kunju, Arul Chinnaiyan, Christopher J. Logothetis, Patricia Troncoso, Nora M. Navone. Analyses of a prostate cancer patient-derived xenografts series, a resource for translational research. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A03.

Monday, August 8, 2016 10:38 AM|Joel|Advanced Prostate Cancer from Malecare|Labels: prostate cancer
One of the terms we hear in the world of cancer is precision medicine. In the area of prostate cancer what does this really mean? Precision medicine is a very broad term, but it can be better described as looking at an individual man’s genetic code and the genetic code of their tumors for the purpose of making treatment decisions. These genetic codes dictate both aggressiveness of the disease as well as the potential efficacy of a drug or treatment. Prostate cancer is a very heterogeneous disease; often each tumor contains multiple genetic structures. In addition, as the tumor spreads […]
Wednesday, August 3, 2016 8:51 PM|Joel|Advanced Prostate Cancer from Malecare|Labels: prostate cancer, cost
CVS Health, a major retail pharmaceutical insurer and supplier has raised some consternation and concerns and it should also raise yours. Last Tuesday, CVS rolled out their 2017 formulary list that left off the some of the world’s top-selling drugs including a vital castrate resistant prostate cancer drug. The pharmacy benefits manager removed from their list Medivation and Astellas’ prostate cancer treatment, Xtandi. They argued that Johnson & Johnson’s Zytiga is also a hormone therapy drug (and is cheaper than Xtandi) could be used in its place. This is a problem as they are not the same drug. Their modes […]
Wednesday, August 3, 2016 12:18 PM|Qu, F., Xie, W., Nakabayashi, M., Zhang, H., Jeong, S. H., Wang, X., Komura, k., Sweeney, C. J., Sartor, O., Lee, G.-S. M., Kantoff, P. W.|Clinical Cancer Research Online First Articles|Labels: prostate cancer

Purpose: We evaluated the association of prostate specific antigen (PSA) and androgen receptor splice variant-7 (AR-V7) transcript levels in patients' blood with time to treatment failure (TTF) and overall survival (OS) with abiraterone acetate (AA) and/or enzalutamide treatment in castration resistant prostate cancer (CRPC) patients. Experimental Design: RNA levels of AR-V7 and PSA in peripheral blood collected before treatment were quantified using Droplet Digital-PCR in retrospective cohorts treated with AA (N=81) or enzalutamide (N=51) for CRPC. Multivariable Cox regression adjusted for known prognostic factors was used for analyses. Results: PSA-transcripts were detected in 57% of AA-treated patients and in 63% of enzalutamide-treated patients. PSA-positive patients had a shorter TTF than PSA-negative patients (adjusted-HR=2.27 (95%CI: 1.26, 4.10) and 2.60 (95%CI: 1.19, 5.69); p-value=0.006 and 0.017 in AA and enzalutamide cohorts, respectively). Patients with a higher-AR-V7 transcript level had a shorter TTF with AA and enzalutamide in univariate analysis (median 8.0 versus 15.6 months, p=0.046 in AA-cohort and 3.6 versus 5.6 months, p=0.050 in enzalutamide-cohort). In multivariable models, the association with TTF remained significant in the enzalutamide-cohort (adjusted-HR=2.02; 95%CI:1.01, 4.05; p=0.048), but statistically insignificant in the AA-cohort. In both cohorts, we observed potential prognostic value of both PSA and AR-V7 RNA expression on OS; patients with detectable PSA transcripts and high AR-V7 predicted the poorest OS. Conclusions: PSA and AR-V7 transcripts in blood potentially serve as biomarkers predicting TTF and OS with AA or enzalutamide treatment. If validated prospectively, their detection could be facilitated without isolation of circulating tumor cells.

Tuesday, August 2, 2016 9:51 AM|Rebello, R. J., Kusnadi, E., Cameron, D. P., Pearson, H. B., Lesmana, A., Devlin, J. R., Drygin, D., Clark, A. K., Porter, L., Pedersen, J., Sandhu, S., Risbridger, G. P., Pearson, R. B., Hannan, R. D., Furic, L.|Clinical Cancer Research Online First Articles|Labels: Myc, prostate cancer

Purpose: The MYC oncogene is frequently over-expressed in prostate cancer (PC). Upregulation of ribosome biogenesis and function is characteristic of MYC-driven tumors. Additionally, PIM kinases activate MYC signaling and mRNA translation in PC and cooperate with MYC to accelerate tumorigenesis. Here, we investigate the efficacy of a single and dual approach targeting ribosome biogenesis and function to treat PC. Experimental Design: The inhibition of ribosomal RNA (rRNA) synthesis with CX-5461, a potent, selective and orally bioavailable inhibitor of RNA polymerase I (Pol I) transcription has been successfully exploited therapeutically, but only in models of hematological malignancy. CX-5461 and CX-6258, a pan-PIM kinase inhibitor, were tested alone and in combination in PC cell lines, in Hi-MYC and PTEN-deficient mouse models and in patient derived xenografts (PDX) of metastatic tissue obtained from a castration-resistant PC patient. Results: CX-5461 inhibited anchorage-independent growth and induced cell cycle arrest in PC cell lines at nanomolar concentrations. Oral administration of 50 mg/kg CX-5461 induced p53 expression and activity and reduced proliferation (Ki-67) and invasion (loss of ductal actin) in Hi-MYC tumors, but not in PTEN null (low MYC) tumors. While 100 mg/kg CX-6258 showed limited effect alone, its combination with CX-5461 further suppressed proliferation and dramatically reduced large invasive lesions in both models. This rational combination strategy significantly inhibited proliferation and induced cell death in PDX of PC. Conclusions: Our results demonstrate preclinical efficacy of targeting the ribosome at multiple levels and provide a new approach for the treatment of PC.

Sunday, July 31, 2016 10:05 PM|Lopez, S. M., Agoulnik, A. I., Zhang, M., Peterson, L. E., Suarez, E., Gandarillas, G. A., Frolov, A., Li, R., Rajapakshe, K., Coarfa, C., Ittmann, M. M., Weigel, N. L., Agoulnik, I. U.|Clinical Cancer Research recent issues|Labels: prostate cancer

Purpose: Castration therapy in advanced prostate cancer eventually fails and leads to the development of castration-resistant prostate cancer (CRPC), which has no cure. Characteristic features of CRPC can be increased androgen receptor (AR) expression and altered transcriptional output. We investigated the expression of nuclear receptor corepressor 1 (NCOR1) in human prostate and prostate cancer and the role of NCOR1 in response to antiandrogens.

Experimental Design: NCOR1 protein levels were compared between matched normal prostate and prostate cancer in 409 patient samples. NCOR1 knockdown was used to investigate its effect on bicalutamide response in androgen-dependent prostate cancer cell lines and transcriptional changes associated with the loss of NCOR1. NCOR1 transcriptional signature was also examined in prostate cancer gene expression datasets.

Results: NCOR1 protein was detected in cytoplasm and nuclei of secretory epithelial cells in normal prostate. Both cytoplasmic and nuclear NCOR1 protein levels were lower in prostate cancer than in normal prostate. Prostate cancer metastases show significant decrease in NCOR1 transcriptional output. Inhibition of LNCaP cellular proliferation by bicalutamide requires NCOR1. NCOR1-regulated genes suppress cellular proliferation and mediate bicalutamide resistance. In the mouse, NCOR1 is required for bicalutamide-dependent regulation of a subset of the AR target genes.

Conclusions: In summary, we demonstrated that NCOR1 function declines with prostate cancer progression. Reduction in NCOR1 levels causes bicalutamide resistance in LNCaP cells and compromises response to bicalutamide in mouse prostate in vivo. Clin Cancer Res; 22(15); 3937–49. ©2016 AACR.

Sunday, July 31, 2016 10:05 PM|Morris, M. J., Rathkopf, D. E., Novotny, W., Gibbons, J. A., Peterson, A. C., Khondker, Z., Ouatas, T., Scher, H. I., Fleming, M. T.|Clinical Cancer Research recent issues|Labels: prostate cancer, clinical trial

Purpose: Preclinical evidence suggests that both docetaxel and enzalutamide target androgen receptor translocation and signaling. This phase Ib study assessed the safety, tolerability, and pharmacokinetics of docetaxel when administered with enzalutamide as first-line systemic chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC).

Experimental Methods: Docetaxel-naïve patients received 21-day cycles of docetaxel (75 mg/m2). Enzalutamide (160 mg/day) was administered daily starting on day 2 of cycle 1. Patients were allowed to stop and restart docetaxel at any time following cycle 2. Treatment continued indefinitely until unacceptable toxicity or discontinuation due to investigator or patient preference.

Results: A total of 22 patients received docetaxel, of whom 21 also received enzalutamide. Docetaxel was administered for a median of 5.0 cycles and enzalutamide for a median of 12.0 months. With concomitant treatment, geometric mean docetaxel exposure decreased by 11.8%, whereas peak concentrations decreased by 3.7% relative to docetaxel alone. The most common toxicities observed during the period of concomitant therapy were neutropenia (86.4%) and fatigue (77.3%). Common toxicities observed with post-docetaxel enzalutamide were constipation (23.8%), decreased appetite (19.0%), fatigue (19.0%), and musculoskeletal pain (19.0%). Treatment with enzalutamide and docetaxel resulted in prostate-specific antigen decreases in almost all patients based on exploratory analysis of available baseline and on-study prostate-specific antigen data.

Conclusions: The combination of docetaxel and enzalutamide is feasible, although higher rates of neutropenia and neutropenic fever than anticipated were observed. Reductions in docetaxel exposure with enzalutamide coadministration were not considered clinically meaningful. This combination warrants further study in a larger mCRPC population. Clin Cancer Res; 22(15); 3774–81. ©2016 AACR.

Thursday, July 28, 2016 7:56 AM|Zarif, J. C., Hernandez, J. R., Pienta, K. J.|Cancer Research recent issues|Labels: prostate cancer
Prostate cancer is a leading cause of cancer-related deaths of men in the U.S., and in the past year, over 30,000 men died from this disease. While localized prostate cancer is highly treatable by surgical resection and radiation, cancer that has metastasized remains incurable. Alternatively activated macrophages, also known as M2-macrophages, primarily scavenge debris and in the process, promote angiogenesis and wound repair. M2-macrophages are phenotypically similar to M2 tumor-associated macrophages (M2-TAMs) have been reported to associate with solid tumors such as prostate cancer to facilitate epithelial to mesenchymal transition (EMT), tumor invasiveness, metastasis, and resistance to therapy. As an invasive species within the tumor microenvironment, this makes M2-TAMs an ideal therapeutic target in prostate cancer. The purpose of this project is to develop novel therapeutics that will directly target M2-TAMs for destruction and subsequently attenuate prostate tumor growth, progression and metastasis. The central hypothesis of this study is to determine if targeting of M2-TAMs using specific surface antigens will be an effective therapy for lethal prostate cancer and potentially, other cancers. Our study elucidated M2-Macrophage biology including creating homogenous populations of both M1 and M2 macrophages using a new strategy as to allow for identification of novel surface antigen markers. We then assessed novel markers of macrophage populations and assessed whether these surface antigens that are expressed on M2-macrophages are also expressed in human prostate cancers indicative of myeloid infiltration. Validation studies using metastatic prostate cancer tissues from rapid autopsies and surgical specimens supplied by the Department of Urology at Johns Hopkins University School of Medicine were also be performed. Complementary studies will be executed to target these markers for anti-tumor cell efficacy using these relevant model systems. By identifying and targeting specific markers on M2-TAMs, we predict that this targeting will provide a better prognosis for patients who have been diagnosed with lethal prostate cancer.Citation Format: Jelani C. Zarif, James R. Hernandez, Kenneth J. Pienta. Targeting M2-tumor associated macrophages (M2-TAMs) in prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B34.
Thursday, July 28, 2016 7:56 AM|Kang, Y. H., Jin, H. A., Heo, J. H., Kim, K. H., Han, K. S., Hong, S. J.|Cancer Research recent issues|Labels: VEGF, prostate cancer
Background: Tumor requires excessive oxygen and nutrients due to their rapid growth. Tumor is generally vascular but the vasculature is not physiologic but leaky, dilated, and tortuous. The inefficiency of tumor vessels induces hypoxic stress that makes the tumor more aggressive. Here, we investigated the role of normalizing tumor vasculature on tumor progression and treatment efficacy of conventional chemotherapy in prostate cancer.Methods: Human vascular endothelial cell (HUVEC) was used to evaluate the effects of SAC-1004 on endothelial cells. Immunofluorescent confocal imaging with immunocytochemistry was performed for E-cadherin expression in HUVECs. MTS assay was performed to assess cell proliferation of HUVECs and PC-3 cells after SAC-1004 treatment. Immunohistochemical staining with anti-CD31 and anti-SMA antibodies was performed to assess vasculature in vivo. PC-3 subcutaneous xenografts were developed to evaluate the effects of SAC-1004 on tumor vasculature and tumor growth in prostate cancer. Magnetic resonance images were taken to assess vascular perfusion in xenografts. SAC-1004 was administrated via tail vein once a day for 7 days. Docetaxel was administrated intravenously once a week.Results: SAC-1004 restored junction protein E-cadherin in vitro in endothelial cells and significantly reduced VEGF-induced retinal vascular leakage. SAC-1004 promoted proliferation of HUVECs in vitro in a dose-dependent manner. However, proliferation of cancer cells was not significantly affected by SAC-1004 treatment. Reduced vascular leakiness and improved hypoxia were found in PC-3 xenografts treated with SAC-1004 treatment and magnetic resonance imaging after SAC-1004 treatment for 7 days confirmed improved perfusion in the PC-3 xenografts treated with SAC-1004 compared with control. Interestingly, SAC-1004 treatment suppressed tumor growth in PC-3 xenografts but SAC-1004 followed by intravenous docetaxel treatment showed the most potent tumor suppression compared with control in PC-3 xenografts.Conclusions: SAC-1004 improves hypoxic tumor microenvironment and restores abnormal leak vasculature of tumor by restoring endothelial cell junction in prostate cancer. Vascular normalization induced tumor regression and docetaxel combination following vascular normalization sensitized prostate cancer to docetaxel treatment.Citation Format: You Hyun Kang, Hyun A Jin, Jun Hyeok Heo, Ki Hong Kim, Kyung Seok Han, Sung Joon Hong. Vascular normalization suppresses tumor progression and potentiates docetaxel chemotherapy in prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B19.
Thursday, July 28, 2016 7:56 AM|Palmer, M., Ma, L., Romsdahl, T., Wei, Q., Loughman, E., Markham, J., Barycki, J., Simpson, M. A.|Cancer Research recent issues|Labels: AR, prostate cancer
Locally advanced and metastatic cancers are frequently treated by androgen deprivation therapy. Tumors that recur despite this treatment, termed castration resistant prostate cancer, are highly aggressive and have acquired the capacity to survive and expand in conditions of low circulating androgens. Prostate epithelial cells control the potency and overall availability of androgen hormones in part by inactivation and excretion of excess quantities. The enzymes that catalyze inactivation, specifically by covalently modifying the hormone with a glucuronate adduct, are called UDP-glucuronosyltransferases (UGT). Genetic mutations that reduce levels of the UGT isozymes needed to eliminate excess androgens from the prostate have been correlated with prostate cancer incidence. The ability to alter androgen elimination at the level of individual cells within a tumor is one mechanism by which tumors become heterogeneous with respect to molecular features and therapeutic resistance.UDP-glucose dehydrogenase (UGDH) catalyzes the NAD+-dependent oxidation of UDP-glucose to UDP-glucuronate, an essential precursor for androgen inactivation by the prostate glucuronidation enzymes UGT2B15 and UGT2B17. Our laboratory has found that non-metastatic prostate tumor cell lines express UGDH in an androgen sensitive manner, that its expression increases the level of UDP-glucuronate, and that these precursors are then channeled to the UGT-catalyzed glucuronidation pathway. The level of UGDH is androgen controlled and serves to regulate tumor cell growth, inversely to its expression. Loss of androgen stimulated UGDH, or pharmacological antagonism of its activity, translated to increased proliferation rate, specifically of androgen dependent tumor cells. We knocked down expression of UGDH in androgen dependent cells to test the role of UGDH in driving cellular glucuronate levels, intratumoral steroid availability, and response to androgen. Flux of UDP sugar metabolites and levels of androgen glucuronide accumulation were compared in control and UGDH knockdown lines by liquid chromatography and mass spectrometry analysis. Effects on androgen sensitive gene expression were monitored by western analysis. Selection of manipulated cells in decremental DHT levels that simulated androgen deprivation was found to reduce steady state UGDH expression, thereby activating the UGT-driven steroid clearance mechanism, as reflected in increased PSA levels and de-repression of UGT2B17. Whereas restimulation of control transfectants with physiological levels of DHT could only increase UGDH expression and maintain full androgen sensitivity in cells experiencing complete androgen loss, the knockdown of UGDH permitted cells to accumulate UDP-glucuronate pools, and decreased UGT-driven glucuronidation of DHT and androsterone. These results support a model in which maintenance of partial UGDH activity through gradual androgen deprivation facilitates loss of sensitivity in androgen elimination pathways and suggests adjuvant UGDH inhibition could prevent or delay onset of castration resistant recurrence.Citation Format: Michelle Palmer, Linlin Ma, Trevor Romsdahl, Qin Wei, Eileen Loughman, Jonathan Markham, Joseph Barycki, Melanie A. Simpson. Altered control of intracellular androgen availability by glucuronidation contributes to loss of androgen dependence in prostate tumor cells. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C41.
Thursday, July 28, 2016 7:56 AM|McGuire, J., Cook, L., Frieling, J., Lynch, C.|Cancer Research recent issues|Labels: prostate cancer
Introduction: Bone metastatic prostate cancer is common, incurable and, hallmarked by extensive osteoblast driven bone formation that greatly impacts the patient's quality of life. To generate new cures a better understanding of the cellular and molecular mechanisms governing prostate cancer-bone interaction are required. Mesenchymal stem cells (MSCs) give rise to multiple cell types including osteoblasts. The bone is a natural reservoir for MSCs and therefore we reasoned that MSCs contribute to the prostate cancer progression and pathophysiology in bone.Rationale/Hypothesis: Our in vitro data identified that MSCs are recruited to prostate cancer derived signals and that human and murine specimens of bone metastatic prostate cancer have an increased amount of MSCs compared tumor naïve controls (α-smooth muscle actin positive). Based on this data, we hypothesized that MSCs contribute to prostate cancer induced osteogenesis.Methodology: Primary MSCs isolated from bone and characterized as CD29+, SCA-1+, CD45- and differentiation capacity were utilized. To mimic bone metastatic prostate cancer, we used an in vivo mouse model (PAIII) of osteogenic bone metastatic prostate cancer. Mice were intratibially inoculated with PAIIIs, PAIIIs/MSCs (1:1), or MSCs (n=8/group, 1x104total cells). Tumor growth was measured at time points using luminescence imaging. Subsequently the tibias were collected for imaging and histological analysis. In vitro, cleaved caspase-3, immunoblot and immunofluorescence were employed to identify mechanisms of MSC-prostate cancer interaction. A resistant clone of the PaIII cell line was derived by multiple rounds of treatment with MSC conditioned media and subsequently used for comparison in vitro and in vivo.Results: Surprisingly, we initially observed that MSCs suppressed PAIII prostate cancer growth in-vivo compared to PAIII alone at day 11 (p<0.05). However, between days 11 and 15, this trend reversed to where MSCs significantly contributed to PAIII growth (p<0.05) suggesting that MSCs could be contributing to the evolution of a resistant or faster growing clone. Tumor bearing tibias were X-rayed and an overall decrease in tumor-induced osteolysis was observed between the PAIII/MSC and PAIII groups. μCT scans and histomorphometry of tumor bearing bones show a significant increase in bone volume in bones injected with PAIII/MSCs when compared to PAIIIs alone (p<0.05). In vitro, PAIII conditioned media promoted MSC differentiation into osteoblasts while MSC conditioned media inhibited PAIII growth by inducing apoptosis. In fact 5-hour exposure significantly enhanced apoptosis as measured by and increase in cleaved caspase-3. Cytokine array analysis and follow up validation indicate roles for MSC derived Fas ligand and IL-28 in promoting prostate cancer cell apoptosis. Of note, successive rounds of MSC conditioned media exposure yielded PAIII cancer cells that were resistant not only to MSC conditioned media but also etoposide and docetaxel induced apoptosis. Further, we observed that in-vivo the MSC educated PAIII cells grew at significantly faster rates than parental PAIII cells.Conclusions: Our data identify MSCs as a major component of osteogenic bone metastatic prostate cancers. Prostate cancer cells promote MSC differentiation into osteoblasts that in turn contributes to the osteogenic nature of the disease. Conversely, MSCs promote the evolution of apoptosis resistant clones that ultimately contribute to tumor progression. Understanding the molecular mechanisms underpinning prostate cancer-MSC interaction could yield exciting therapeutic opportunities to eradicate incurable bone metastatic prostate cancer.Citation Format: Jeremy McGuire, Leah Cook, Jeremy Frieling, Conor Lynch. Mesenchymal stem cells in the prostate cancer-bone microenvironment increase osteogenesis and generate apoptotic resistant cancer cells. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C18.
Thursday, July 28, 2016 7:56 AM|Jin, W., Zhao, A., Levesque, C., Colman, I., Nelson, P. S.|Cancer Research recent issues|Labels: prostate cancer
Background: Radiation and chemotherapeutics have significantly improved the survival rate among cancer patients although resistance to both treatment approaches commonly develops, particularly in the setting of metastatic disease. It is now recognized that tumor microenvironments (TME) can profoundly influence responses to cytotoxic /genotoxic insults and also alter effective immune-mediated tumor eradication. Major efforts are underway to understand how to improve tumor cell killing within the complex microenvironment of a tumor where tumor-mediated immune suppressive mechanisms have been documented to attenuate immune attack. Senescent/damaged cells have been shown to activate the expression of proinflammatory cytokines, tumor promoting growth factors and proteases which collectively encompass a DNA damage induced secretory program (DDSP). Our preliminary data indicate that genotoxic therapeutics may also generate an immune suppressive microenvironment that could impair an effective immune attack. In this study, we sought to identify the key drivers in the DDSP which hamper the effective-ness of anti-tumor immune responses.Methods: In this study, we adopted a syngeneic mouse xenograft model to investigate the influence of the DDSP on the immune landscape within the tumor microenvironment (TME) of local and metastatic sites. The Myc-Cap prostate cancer cell line and F4M2 prostate fibroblast line are both derived from FVB mice. We treated F4M2 cells with irradiation (RAD) or genotoxic drugs to induce the DDSP in vitro. The conditional medium (CM) was applied in assays to test the function of different populations of tumor infiltrating lymphocytes (TIL). To further pinpoint the role of Wnt16b, a major component of the DDSP, recombinant protein was used to assess lymphocyte responses.Results: We hypothesized that the TME DDSP, which is induced by cancer-directed genotoxic treatment, hampers anti-tumor effects by generating an immune suppressive environment. We demonstrated that upon receiving irradiation, DDSP signature genes (IL-6, Wnt16b) were activated in prostate tissue as well as common sites for metastatic prostate cancers. We demonstrated that RAD treated F4M2 CM inhibited T cell proliferation as well as cytotoxic functions of CD8 cells. We further identified that Wnt16b is a key immunosuppressive factor in the CM. In xenograft models, mice transplanted with Myc-Cap/RAD-F4M2 grafts developed significantly larger tumors compared to those receiving sham-treated cell graft (1500mm3 vs. 1023mm3, p=0.039). Mice from the former group exhibited elevated myeloid derived suppressor cells in the periphery as well as reduced numbers of CD8 T cells in the TME.Conclusions: The DDSP, and particularly the DDSP component Wnt16b, contributes to treatment resistance not only by supporting tumor growth but also creating an immune suppressive TME. Inhibiting the DDSP may enhance anti-tumor effects via the relief of immune suppression.Citation Format: Wei Jin, Aric Zhao, Christine Levesque, Ilsa Colman, Peter S. Nelson. Targeting immunosuppressive alterations in the tumor microenvironment resulting from therapy-induced DNA damage responses. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A04.
Wednesday, July 27, 2016 11:11 AM|SINHA, A. A., POMROY, F. E., WILSON, M. J.|Anticancer Research recent issues|Labels: AR, prostate cancer

Background/Aim: About 80 to 90% of prostate cancer (PCa) is androgen-dependent at diagnosis, but patients ultimately develop castration-resistant prostate cancer (CRPC), which is usually not amenable to androgen deprivation (ablation) therapy (ADT). Patients with CRPC usually succumb to death in less than 5 years and there is no cure. Here, we investigated reasons for ADT failure. Materials and Methods: Biopsy specimens from untreated and diethylstilbestrol (DES)-treated patients were assessed for localization of antibody IgGs against androgen (AR) and estrogen (ER) receptors. Results: In untreated and DES-treated sections, methylene blue stained basic proteins in dark basal (undifferentiated) PCa cells, whereas light basal cells were not stained. AR localized to light basal cells which showed widespread degeneration in sections from DES-treated patients, indicating their dependence on androgen. In contrast, dark basal cells did not show widespread degeneration in DES-treated patients; ER was usually localized in dark cells. The number of dark cells progressively increased in DES-treated patients indicating their androgen-independence. The localization of AR and ER in some light and dark basal cells indicated that the supply of androgen/estrogen was not inhibited during ADT. Dark basal cells had emerged prior to treatment and proliferated during DES treatment, that also indicated their androgen-independence. Conclusion: PCa has at least two populations of cells: androgen-dependent light basal and estrogen-dependent dark basal cells. ADT did not destroy estrogen-dependent cells which may have given rise to CRPC tumors. Therefore, ADT is an incomplete treatment. For a more complete treatment of PCa, we recommend concurrent androgen and estrogen ablation, together with the inhibition of selected steroid biosynthetic enzymes.

Tuesday, July 26, 2016 6:08 AM|Google News on 'cancer for a feed'|Labels: prostate cancer, clinical trial, financial


Tokai Pharma Shutters Prostate Cancer Drug Trial Early, Shares Crumble
Cambridge, MA-based Tokai (NASDAQ: TKAI) said that an independent data monitoring committee instructed the company to stop the big Phase 3 trial of its prospective prostate cancer drug, galeterone, early because the study was likely to fail: Galeterone ...

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Monday, July 25, 2016 10:44 AM|Shourideh, M., Azabdaftari, G., Attwood, K., DePriest, A., Wadosky, K. M., Gillard, B. M., Karasik, E., Heemers, H., Kyprianou, N., Gelman, I. H., Corey, E., Vessella, R. L., Mohler, J. L., Koochekpour, S.|Clinical Cancer Research Online First Articles|Labels: AR, prostate cancer

Purpose:We recently demonstrated that glutamate receptor GRM1 was expressed at high levels in castration-resistant prostate cancer (CR-PCa) tissues and cells. Herein, we determined the relationship between GRM1 and AR, PSA, and tumor growth, remission, and recurrence in preclinical PCa models. The effect of alterations in GRM1 expression was also investigated on PCa cell growth, migration and invasion. Experimental Design:We used quantitative gene expression and immunohistochemistry to define the temporal association between GRM1 expression and AR, PSA, and tumor growth during CR progression in CWR22 (n = 59) and LuCaP 35 (n = 12) PCa xenografts. The effect of alterations in GRM1 expression levels on growth, migration, and invasion was investigated in GRM1-overexpressed or -silenced PCa cell lines. The effect of DHT on GRM1 expression was determined in the presence or absence of the antiandrogen bicalutamide. Results:We found that GRM1 transcript and tissue expression directly correlated with growth and AR and PSA expression in hormone-sensitive (HS), castrated, and CR tumor xenografts. GRM1 overexpression or silencing directly correlated with PCa cell proliferation, migration, and invasion. DHT increased GRM1 expression via an AR-dependent manner in HS- and CR-PCa cell lines. Conclusions:This is a first report of GRM1 as an androgen and AR-target gene. GRM1 expression directly correlated with tumor growth, regression, and recurrence and may contribute to CR-progression of PCa in preclinical models. Further studies are needed to define the utility of GRM1 as a druggable target or biomarker for PCa.

CONCLUSIONSThis is likely the first randomized trial of multimarker genomic testing to report genomic targeting of cancer screening. This study found little evidence of concern about excess anxiety or overuse/underuse of PSA screening when multimarker genetic risks were provided to patients. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Wednesday, July 20, 2016 9:31 AM|Saylor, P. J., Lee, R. J., Arora, K. S., Deshpande, V., Hu, R., Olivier, K., Meneely, E., Rivera, M. N., Ting, D. T., Wu, C.-L., Miyamoto, D. T.|Clinical Cancer Research Online First Articles|Labels: prostate cancer, biomarker diagnostic

Purpose: The androgen receptor (AR) mRNA splice variant AR-V7 has emerged as a predictive biomarker for response to AR targeted therapies. There are currently no commercially available assays to detect AR splice variants. The branched chain RNA in situ hybridization (ISH) platform enables the highly sensitive detection of RNA transcripts in formalin-fixed, paraffin-embedded (FFPE) tissues. Experimental Design: We designed a branched chain RNA ISH probe to target the unique cryptic exon CE3 of AR-V7 using multiple tiling probes. This automated ISH assay was applied to tumor tissue from two distinct clinical cohorts that we hypothesized would differ in AR-V7 status. Results: We detected AR-V7 in all tumor samples from men with metastatic castration-resistant prostate cancer with tissue obtained after disease progression despite at least one subsequent line of hormonal therapy (abiraterone, enzalutamide, or bicalutamide; n=12). We detected AR-V7 in just one tumor from men who had undergone prostatectomy for localized adenocarcinoma (n=30; Gleason 4+5=9 in the AR-V7 positive sample). Given the apparent distinction between the above groups by AR-V7 signal, we analyzed pre-treatment AR-V7 status as a predictive and prognostic biomarker in men with treatment-naive metastatic disease. Patients with metastases but without detectable AR-V7 RNA at baseline had significantly longer overall survival (logrank P = 0.044) and a trend toward superior progression-free survival (logrank P = 0.055). Conclusions: Within an institutional cohort, the RNA ISH assay identified AR-V7 within FFPE tissue and may have prognostic value in metastatic castration-sensitive prostate cancer. These preliminary findings warrant further study in larger cohorts.

Thursday, July 14, 2016 10:05 PM|Gao, S., Ye, H., Gerrin, S., Wang, H., Sharma, A., Chen, S., Patnaik, A., Sowalsky, A. G., Voznesensky, O., Han, W., Yu, Z., Mostaghel, E. A., Nelson, P. S., Taplin, M.-E., Balk, S. P., Cai, C.|Clinical Cancer Research recent issues|Labels: AR, EGFR, prostate cancer

Purpose: ErbB2 signaling appears to be increased and may enhance androgen receptor (AR) activity in a subset of patients with castration-resistant prostate cancer (CRPC), but agents targeting ErbB2 have not been effective. This study was undertaken to assess ErbB2 activity in abiraterone-resistant prostate cancer and to determine whether it may contribute to AR signaling in these tumors.

Experimental Design: AR activity and ErbB2 signaling were examined in the radical prostatectomy specimens from a neoadjuvant clinical trial of leuprolide plus abiraterone and in the specimens from abiraterone-resistant CRPC xenograft models. The effect of ErbB2 signaling on AR activity was determined in two CRPC cell lines. Moreover, the effect of combination treatment with abiraterone and an ErbB2 inhibitor was assessed in a CRPC xenograft model.

Results: We found that ErbB2 signaling was elevated in residual tumor following abiraterone treatment in a subset of patients and was associated with higher nuclear AR expression. In xenograft models, we similarly demonstrated that ErbB2 signaling was increased and associated with AR reactivation in abiraterone-resistant tumors. Mechanistically, we show that ErbB2 signaling and subsequent activation of the PI3K/AKT signaling stabilizes AR protein. Furthermore, concomitantly treating CRPC cells with abiraterone and an ErbB2 inhibitor, lapatinib, blocked AR reactivation and suppressed tumor progression.

Conclusions: ErbB2 signaling is elevated in a subset of patients with abiraterone-resistant prostate cancer and stabilizes AR protein. Combination therapy with abiraterone and ErbB2 antagonists may be effective for treating the subset of CRPC with elevated ErbB2 activity. Clin Cancer Res; 22(14); 3672–82. ©2016 AACR.

Thursday, July 14, 2016 3:00 PM|Current Pharmaceutical Design|Current Pharmaceutical Design via|Comments|Labels: prostate cancer
Authors: da Silva LC, do Carmo FA, Nasciutti LE, Zancan P, Sathler PC, Cabral LM Abstract Prostate cancer remains an increasingly common malignancy worldwide. Many advances in drug development have been achieved for the conventional treatments; however, chemotherapeutic agents are distributed nonspecifically in the body where they affect both prostate cancer and healthy cells. Limited dose achievable within the prostate tumor and suboptimal treatment due to excessive toxicities reveal the importance of the development of more specific mechanisms and ways of drug targeting to prostate tumor. In this context, nanotechnology, molecular biology and biochemistry have been applied in the pharmaceutical area for development of new targeted drug delivery nanosystems in order to improve its...
Tuesday, July 12, 2016 11:23 AM|News-Medical.Net VEGF News Feed|Comments|Labels: prostate cancer, clinical trial
A recently published international clinical Phase III trial of a promising drug for treating advanced prostate cancer ended with surprising results: the new therapeutic agent failed to achieve any significant improvement in the overall survival of patients compared with the established standard treatment.
Tuesday, July 12, 2016 6:00 AM|Prostate / Prostate Cancer News From Medical News Today|Labels: prostate cancer, clinical trial
A recently published international clinical Phase III trial of a promising drug for treating advanced prostate cancer ended with surprising results: the new therapeutic agent failed to achieve any...
Monday, July 11, 2016 1:55 PM|Sperger, J. M., Strotman, L. N., Welsh, A., Casavant, B. P., Chalmers, Z., Horn, S., Heninger, E., Thiede, S., Tokar, J., Gibbs, B. K., Guckenberger, D. J., Carmichael, L., Dehm, S. M., Stephens, P. J., Beebe, D. J., Berry, S. M., Lang, J. M.|Clinical Cancer Research Online First Articles|Labels: AR, prostate cancer, biomarker diagnostic

PURPOSE: There is a critical clinical need for new predictive and pharmacodynamic biomarkers that evaluate pathway activity in patients treated with targeted therapies. A microscale platform known as VERSA (Versatile Exclusion-based Rare Sample Analysis) was developed to integrate readouts across protein, mRNA and DNA in Circulating Tumor Cells (CTCs) for a comprehensive analysis of the Androgen Receptor (AR) signaling pathway. EXPERIMENTAL DESIGN: Utilizing exclusion based sample preparation principles, a handheld chip was developed to perform CTC capture, enumeration, quantification and subcellular localization of proteins and extraction of mRNA and DNA. This technology was validated across integrated endpoints in cell lines and a cohort of patients with castrate resistant prostate cancer (CRPC) treated with AR targeted therapies and chemotherapies. RESULTS: The VERSA was validated in cell lines to analyze AR protein expression, nuclear localization and gene expression targets. When applied to a cohort of patients, radiographic progression was predicted by the presence of multiple AR splice variants and activity in the canonical AR signaling pathway. AR protein expression and nuclear localization identified phenotypic heterogeneity. Next Generation Sequencing with the FoundationOne panel detected copy number changes and point mutations. Longitudinal analysis of CTCs identified acquisition of multiple AR variants during targeted treatments and chemotherapy. CONCLUSIONS: Complex mechanisms of resistance to AR targeted therapies, across RNA, DNA and protein endpoints, exist in patients with CRPC and can be quantified in CTCs. Interrogation of the AR signaling pathway revealed distinct patterns relevant to tumor progression and can serve as pharmacodynamic biomarkers for targeted therapies.

Wednesday, July 6, 2016 6:00 PM|Alessandro Sciarra|Cancers|Labels: prostate cancer
In cancer patients, the immune system is often altered with an excess of inhibitory factors, such as immunosuppressive cytokines, produced by regulatory T cells (Treg) or myeloid-derived suppressor cells (MDSC). The manipulation of the immune system has emerged as one of new promising therapies for cancer treatment, and also represents an attractive strategy to control prostate cancer (PCa). Therapeutic cancer vaccines and immune checkpoint inhibitors have been the most investigated in clinical trials. Many trials are ongoing to define the effects of immune therapy with established treatments: androgen deprivation therapy (ADT) and chemotherapy (CT) or radiotherapy (RT). This article discusses some of these approaches in the context of future treatments for PCa.
Friday, July 1, 2016 6:00 AM|Prostate / Prostate Cancer News From Medical News Today|Labels: prostate cancer
Ferring Pharmaceuticals announced today that the National Institute for Health and Care Excellence (NICE) has recommended FIRMAGON® (degarelix) for a group of men with advanced...
Thursday, June 30, 2016 10:05 PM|Chua, M. L. K., Bristow, R. G.|Clinical Cancer Research recent issues|Labels: AR, prostate cancer

Androgen suppression mediates transcriptional downregulation of DNA repair genes. Stimulation with supraphysiologic levels of dihydrotestosterone induces formation of lethal DNA breaks through recruitment of topoisomerase II enzymes to fragile DNA sites. Bipolar castration and stimulation that contributes to increasing DNA damage represents a novel strategy of sensitizing prostate cancer to cytotoxic therapies, including radiotherapy. Clin Cancer Res; 22(13); 3124–6. ©2016 AACR.

See related article by Hedayati et al., p. 3310

Wednesday, June 29, 2016 9:30 AM|Zhao, S., Geybels, M. S., Leonardson, A., Rubicz, R., Kolb, S., Yan, Q., Klotzle, B., Bibikova, M., Hurtado-Coll, A., Troyer, D., Lance, R., Lin, D., Wright, J. L., Ostrander, E. A., Fan, J.-B., Feng, Z., Stanford, J. L.|Clinical Cancer Research Online First Articles|Labels: prostate cancer, biomarker diagnostic

Purpose: Aside from Gleason sum few factors accurately identify the subset of prostate cancer (PCa) patients at high risk for metastatic progression. We hypothesized that epigenetic alterations could distinguish prostate tumors with life-threatening potential. Experimental Design: Epigenome-wide DNA methylation profiling was performed in surgically resected primary tumor tissues from a population-based (n = 430) and a replication (n = 80) cohort of PCa patients followed prospectively for at least five years. Metastasis was confirmed by positive bone scan, MRI, CT or biopsy, and death certificates confirmed cause of death. AUC, partial AUC (pAUC, 95% specificity), and P-value criteria were used to select differentially methylated CpG sites that robustly stratify patients with metastatic-lethal from non-recurrent tumors, and which were complementary to Gleason sum. Results: Forty-two biomarkers stratified patients with metastatic-lethal versus non-recurrent PCa in the discovery cohort, and eight of these CpGs replicated in the validation cohort based on a significant (P <0.05) AUC (range: 0.66-0.75) or pAUC (range: 0.007-0.009). The biomarkers that improved discrimination of patients with metastatic-lethal PCa include CpGs in five genes (ALKBH5, ATP11A, FHAD1, KLHL8, and PI15) and three intergenic regions. In the validation dataset the AUC for Gleason sum alone (0.82) significantly increased with the addition of four individual CpGs (range: 0.86-0.89; all P <0.05). Conclusions: Eight differentially methylated CpGs that distinguish patients with metastatic-lethal from non-recurrent tumors were validated. These novel epigenetic biomarkers warrant further investigation as they may improve prognostic classification of patients with clinically localized PCa and provide new insights on tumor aggressiveness.

Tuesday, June 28, 2016 8:41 AM|Chen, X., Li, Q., Liu, X., Liu, C., Liu, R., Rycaj, K., Zhang, D., Liu, B., Jeter, C., Calhoun-Davis, T., Lin, K., Lu, Y., Chao, H.-P., Shen, J., Tang, D. G.|Clinical Cancer Research Online First Articles|Labels: prostate cancer

Purpose: We have shown that the phenotypically undifferentiated (PSA–/lo) prostate cancer cell population harbors long-term self-renewing cancer stem cells (CSC) that resist castration, and a subset of the cells within the PSA–/lo population bearing the ALDHhiCD44+α2β1+ phenotype (Triple Marker+/TM+) is capable of robustly initiating xenograft tumors in castrated mice. The goal of the current project is to further characterize the biologic properties of TM+ prostate cancer cell population, particularly in the context of initiating and propagating castration-resistant prostate cancer (CRPC).

Experimental Design: The in vivo CSC activities were measured by limiting-dilution serial tumor transplantation assays in both androgen-dependent and androgen-independent prostate cancer xenograft models. In vitro clonal, clonogenic, and sphere-formation assays were conducted in cells purified from xenograft and patient tumors. qPCR, Western blot, lentiviral-mediated gene knockdown, and human microRNA arrays were performed for mechanistic studies.

Results: By focusing on the LAPC9 model, we show that the TM+ cells are CSCs with both tumor-initiating and tumor-propagating abilities for CRPC. Moreover, primary patient samples have TM+ cells, which possess CSC activities in "castrated" culture conditions. Mechanistically, we find that (i) the phenotypic markers are causally involved in CRPC development; (ii) the TM+ cells preferentially express castration resistance and stem cell–associated molecules that regulate their CSC characteristics; and (iii) the TM+ cells possess distinct microRNA expression profiles and miR-499-5p functions as an oncomir.

Conclusions: Our results define the TM+ prostate cancer cells as a population of preexistent stem-like cancer cells that can both mediate and propagate CRPC and highlight the TM+ cell population as a therapeutic target. Clin Cancer Res; 1–12. ©2016 AACR.

Wednesday, June 15, 2016 10:56 AM|Bansal, N., Bartucci, M., Yusuff, S., Davis, S., Flaherty, K., Huselid, E., Patrizii, M., Jones, D., Cao, L., Sydorenko, N., Moon, Y.-C., Zhong, H., Medina, D., Kerrigan, J., Stein, M. N., Kim, I. Y., Davis, T. W., DiPaola, R. S., Bertino, J., Sabaawy, H. E.|Clinical Cancer Research Online First Articles|Labels: prostate cancer

Purpose: Current prostate cancer (PCa) management calls for identifying novel and more effective therapies. Self-renewing tumor-initiating cells (TICs) hold intrinsic therapy-resistance and account for tumor relapse and progression. As BMI-1 regulates stem cell self-renewal, impairing BMI-1 function for TICs-tailored therapies appears to be a promising approach. Experimental design: We have previously developed a combined immunophenotypic and time-of-adherence assay to identify CD49bhiCD29hiCD44hi cells as human prostate TICs. We utilized this assay with patient derived prostate cancer cells and xenograft models to characterize the effects of pharmacological inhibitors of BMI-1. Results: We demonstrate that in cell lines and patient-derived TICs, BMI-1 expression is upregulated and associated with stem cell-like traits. From a screened library, we identified a number of post-transcriptional small molecules that target BMI-1 in prostate TICs. Pharmacological inhibition of BMI-1 in patient-derived cells significantly decreased colony formation in vitro and attenuated tumor initiation in vivo, thereby functionally diminishing the frequency of TICs, particularly in cells resistant to proliferation- and androgen receptor (AR)-directed therapies, without toxic effects on normal tissues. Conclusions: Our data offer a paradigm for targeting TICs and support the development of BMI-1-targeting therapy for a more effective PCa treatment.

Monday, June 6, 2016 4:58 AM|ONISHI, T., SHIBAHARA, T., MASUI, S., SUGINO, Y., HIGASHI, S., SASAKI, T.|Anticancer Research recent issues|Labels: prostate cancer

Background: There has recently been renewed interest in the use of estrogens as a treatment strategy for castration-resistant prostate cancer (CRPC). The purpose of this study was to evaluate the feasibility and efficacy of ethinylestradiol re-challenge (re-EE) in the management of CRPC. Patients and Methods: Patients with metastatic CRPC who received re-EE after disease progression on prior EE and other therapy were retrospectively reviewed for prostate-specific antigen (PSA) response, PSA progression-free survival (P-PFS) and adverse events. Results: Thirty-six re-EE treatments were performed for 20 patients. PSA response to the initial EE treatment was observed in 14 (70%) patients. PSA response to re-EE was 33.3% in 36 re-EE treatments. The median P-PFS for patients treated with initial and re-EE was 7 months and 4 months, respectively. Interestingly, PSA response to re-EE was observed even in non-responders to initial EE, and those treated with multiple re-EE. No patients developed cardiovascular or thromboembolic events. Conclusion: Re-EE may be safely repeated several times and can lead to a prolonged disease control in selected patients. Re-challenge with EE appears to be a reasonable option worth considering for patients with metastatic CRPC.

Monday, June 6, 2016 4:58 AM|GRISANTI, S., ANTONELLI, A., BUGLIONE, M., ALMICI, C., FORONI, C., SODANO, M., TRIGGIANI, L., GRECO, D., PALUMBO, C., MARINI, M., MAGRINI, S. M., BERRUTI, A., SIMEONE, C.|Anticancer Research recent issues|Labels: prostate cancer, clinical trial

Background: Circulating tumor cells have been described in prostate cancer patients at diagnosis and in the metastatic phase but little is known on their role at biochemical PSA recurrence. Patients and Methods: Patients radically cured with either prostatectomy or radiotherapy were sequentially included at PSA recurrence. The presence of CTCs was evaluated by the CellSearch system. Results: Twenty-nine patients were accrued at PSA recurrence. Median PSA at recurrence was 7.2 ng/ml (range=3.86-51.0 ng/ml). The median time to PSA progression was 4.66 years (range=0.1-16 years). CTCs were detected in one patient (3%) with low numbers (1 CTC/7.5 ml). Conclusion: In patients radically cured for prostate cancer at biochemical recurrence, CTCs are detected at very low levels in a minority of patients. Further studies are required to investigate alternative methods of CTC detection and the possible role of the bone marrow pre-metastatic niche at biochemical recurrence.

Thursday, June 2, 2016 10:05 PM|Unknown Author|Cancer Discovery recent issues|Labels: prostate cancer

New research indicates a potential therapeutic target for castration-resistant prostate cancer: ROR, which is abundant in the disease, can drive androgen receptor hyperactivity. Blocking ROR with small-molecule antagonists suppresses AR and impedes tumor growth in mice bearing human prostate tumors, including a model resistant to the antiandrogen enzalutamide.

Thursday, June 2, 2016 10:05 PM|Unknown Author|Cancer Discovery recent issues|Labels: AR, prostate cancer

Surgical castration synergizes with immunotherapy, but chemical castration has suppressive effects.

Wednesday, June 1, 2016 1:00 AM|Honn, K. V., Guo, Y., Cai, Y., Lee, M.-J., Dyson, G., Zhang, W., Tucker, S. C.|The FASEB Journal recent issues|Labels: prostate cancer, clinical trial

Previously we identified and deorphaned G-protein-coupled receptor 31 (GPR31) as the high-affinity 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] receptor (12-HETER1). Here we have determined its distribution in prostate cancer tissue and its role in prostate tumorigenesis using in vitro and in vivo assays. Data-mining studies strongly suggest that 12-HETER1 expression positively correlates with the aggressiveness and progression of prostate tumors. This was corroborated with real-time PCR analysis of human prostate tumor tissue arrays that revealed the expression of 12-HETER1 positively correlates with the clinical stages of prostate cancers and Gleason scores. Immunohistochemistry analysis also proved that the expression of 12-HETER1 is positively correlated with the grades of prostate cancer. Knockdown of 12-HETER1 in prostate cancer cells markedly reduced colony formation and inhibited tumor growth in animals. To discover the regulatory factors, 5 candidate 12-HETER1 promoter cis elements were assayed as luciferase reporter fusions in Chinese hamster ovary (CHO) cells, where the putative cis element required for gene regulation was mapped 2 kb upstream of the 12-HETER1 transcriptional start site. The data implicate 12-HETER1 in a critical new role in the regulation of prostate cancer progression and offer a novel alternative target for therapeutic intervention.—Honn, K. V., Guo, Y., Cai, Y., Lee, M.-J., Dyson, G., Zhang, W., Tucker, S. C. 12-HETER1/GPR31, a high-affinity 12(S)-hydroxyeicosatetraenoic acid receptor, is significantly up-regulated in prostate cancer and plays a critical role in prostate cancer progression.

Tuesday, May 31, 2016 10:00 AM|Prostate / Prostate Cancer News From Medical News Today|Labels: prostate cancer, biomarker diagnostic
The U.S. Food and Drug Administration has approved Axumin, a radioactive diagnostic agent for injection.
Thursday, May 26, 2016 6:59 AM|Kiess, A., Minn, I., Vaidyanathan, G., Hobbs, R. F., Josefsson, A., Shen, C., Brummet, M., Chen, Y., Choi, J., Koumarianou, E., Baidoo, K., Brechbiel, M., Mease, R. C., Sgouros, G., Zalutsky, M. R., Pomper, M.|JNM Ahead of Print|Labels: prostate cancer

Introduction: Alpha particle emitters have a high linear energy transfer and short range, offering the potential for treating micrometastases while sparing normal tissues. We developed a urea-based, 211At-labeled small-molecule targeting prostate-specific membrane antigen (PSMA) for treatment of micrometastases due to prostate cancer (PC). Methods: PSMA-targeted (2S)-2-(3-(1-carboxy-5-(4-[211At]astatobenzamido)pentyl)ureido)-pentanedioic acid ([211At]6) was synthesized. Cellular uptake and clonogenic survival were tested in PSMA-positive (PSMA+) PC3 PIP and PSMA-negative (PSMA-) PC3 flu human PC cells after [211At]6 treatment. Anti-tumor efficacy of [211At]6 was evaluated in mice bearing PSMA+ PC3 PIP and PSMA- PC3 flu flank xenografts at a 740 kBq dose, and in mice bearing PSMA+, luciferase-expressing PC3-ML micrometastases. Biodistribution was determined in mice bearing PSMA+ PC3 PIP and PSMA- PC3 flu flank xenografts. Sub-organ distribution was evaluated using α-Camera images, and micro-scale dosimetry was modeled. Long-term toxicity was assessed in mice for 12 mo. Results: [211At]6 treatment resulted in PSMA-specific cellular uptake and decreased clonogenic survival in PSMA+ PC3 PIP cells, and caused significant tumor growth delay in PSMA+ PC3 PIP subcutaneous tumors. Significantly improved survival was achieved in the newly developed PSMA+ micrometastatic PC model. Biodistribution showed uptake of [211At]6 in PSMA+ PC3 PIP tumors and in kidneys. Micro-scale kidney dosimetry based on α-Camera images and a nephron model revealed hot spots in the proximal renal tubules. Long-term toxicity studies confirmed that the dose-limiting toxicity was late radiation nephropathy. Conclusion: PSMA-targeted [211At]6 α-particle radiotherapy yielded significantly improved survival in mice bearing PC micrometastases after systemic administration. [211At]6 also showed uptake in renal proximal tubules resulting in late nephrotoxicity, highlighting the importance of long-term toxicity studies and micro-scale dosimetry.

CONCLUSIONSFor patients who predominantly have IRPC, the addition of HT to DE‐EBRT did not significantly affect BF, OS, or LC. Bicalutamide appeared to be well tolerated. The conclusions from the study are limited by incomplete recruitment. Cancer 2016;122:2595–603. © 2016 American Cancer Society. (Source: Cancer)
Monday, May 16, 2016 1:00 AM|Prostate / Prostate Cancer News From Medical News Today|Labels: prostate cancer
New study finds genetic alterations in the VAC14 gene are associated with an increased risk of docetaxel-induced peripheral neuropathy in prostate cancer patients.
Monday, May 9, 2016 11:00 AM|Prostate / Prostate Cancer News From Medical News Today|Labels: BRCA, prostate cancer
Though predominantly known for their increased associations with breast cancer risk, germline mutations in the BRCA1 and BRCA2 genes are also associated with an increased susceptibility to other...
Monday, May 9, 2016 8:00 AM|Prostate / Prostate Cancer News From Medical News Today|Labels: prostate cancer
A study using Swedish data finds men prescribed testosterone for over a year had no overall rise in prostate cancer risk, and they showed a 50 percent fall in aggressive disease.
Wednesday, April 20, 2016 7:00 AM| (Taylor Patton)|Cancer|Labels: prostate cancer, clinical trial

Medically reviewed by T. Rhett Spencer, MD McLeod Health Radiation Oncology

For a man, the diagnosis of Prostate Cancer can be devastating. The concern is not so much for his ultimate survival (five-year survival rates are almost 100%; and at 10 years, almost 99%.). It’s the specter of potential treatment side effects that strike directly at his “manhood” -- possible incontinence and erectile dysfunction.

“Newer treatments, plus technical advances in surgery and radiation therapy, can reduce the side effects,” says McLeod Radiation Oncologist Dr. T. Rhett Spencer.  “Understanding the signs and symptoms of prostate cancer is important, because early treatment can also help limit the side effects.”


The prostate gland is about the size of a walnut and is on either side of the opening that empties urine from the bladder.

These signs may indicate prostate cancer, but also may reflect other health issues.

  • Weak or stop-and-go urine stream
  • Sudden or frequent urge to urinate
  • Pain, burning or blood when urinating
  • Hip, back or pelvic pain that doesn’t go away.

Prostate cancer is detected mostly in older men. Overall, about 1 in 5 men will ultimately be diagnosed with prostate cancer. If you are experiencing the above prostate cancer symptoms, see your personal physician or a urologist to conduct tests. 


Watchful Waiting (or Active Surveillance) is unique to Prostate Cancer. The tumors in this organ are usually very slow growing and doctors don’t want to intervene unless the cancer appears to be growing fast or is in danger of spreading. In this case, the specialist continues to see the patient on a regular basis. A variety of tests are performed. If and when appropriate, the physician may recommend moving to a more aggressive treatment phase.

Like most other cancers, tumors in the prostate can be treated by radiation therapy or surgery. Modern developments, such as Stereotactic Body Radiation Therapy (SBRT), use very highly focused radiation beams, resulting in fewer radiation sessions needed.

Internal radiation therapy (brachytherapy) can also be delivered by injecting small radioactive beads into the tumor. It's generally limited to men with slow-growing, early-stage tumors.

In addition, surgeons can perform a Radical Prostatectomy to remove the prostate, using minimally invasive techniques that require only a few small incisions. Patients have less pain and speedier recovery than with traditional surgery.


Incontinence, urinary problems or leakage are the primary side effects of treatment for prostate cancer. After surgery, some 25% of patients have a problem. After external radiation, about 45% of men have urinating problems but most of those problems resolve after a year. Internal radiation treatment results in 70% of men needing pads or medications. But that may drop to about 30% over time.

For more information on Incontinence & Prostate Cancer, check here.

Difficulty in having an erection (erectile dysfunction) is a problem in almost all men following treatment, although age, the ability to get an erection before treatment and whether the nerves controlling erection were affected by surgery may impact erectile dysfunction. 

Radiation and surgery have a traumatic effect on the delicate nerves and blood vessel that control the physical aspects of erection, not to mention the impact on a man’s mental and emotional state. Two years after surgery, 30% to 60% of men will return to pre-treatment function. After external radiation therapy, about 50% of men have erectile dysfunction problems, but they improve over time. With internal radiation therapy, the number of men who experience erection problems is lower, but it does not improve over time.


For more information on Sexuality & Prostate Cancer, check here.

Ask a Cancer Specialist a question.

Sources include: McLeod Health, National Institutes of Health, Prostate Cancer Foundation, Journal of Clinical Oncology, American Cancer Society


Tuesday, March 29, 2016 12:07 AM|Cancer|Cancer via|Comments|Labels: mTOR, prostate cancer, clinical trial
CONCLUSIONSThe combination of bicalutamide and everolimus has encouraging efficacy in men with bicalutamide‐naive CRPC, thus warranting further investigation. A substantial number of patients experienced everolimus‐related toxicity. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Multiparametric MRI has emerged as a popular imaging modality to localize prostate cancer. Nevertheless, interpretation of MRI is subjective, with concerns for false positives, particularly in the transitional zone (TZ), where hyperplastic changes that are common to this region may be confused for suspicion of cancer. We analyzed a prospective cohort of men undergoing MRI-US fusion biopsy and compared cancer detection rate between lesions seen in the peripheral zone (PZ) and the TZ. (Source: The Journal of Urology)

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NY-ESO-1 antigen is a cancer-testis antigen that is exclusively expressed in several types of cancer, aside from expression in the normal testis and placenta. This antigen is considered an ideal target for cancer immunotherapy. Cholesteryl pullulan (CHP) is a novel antigen delivery system. Complexes of CHP and NY-ESO-1 antigen (CHP-NY-ESO-1) present multiple epitope peptides to both the MHC class I and class II pathways. MIS416 is a non-toxic microparticle adjuvant that activates immune responses via NOD-2 and TLR9 pathways. (Source: The Journal of Urology)
Tuesday, March 22, 2016 10:51 AM|Hu, D., Hu, W., Majumdar, S., Gauntner, T., Li, Y., Shi, G., Kasper, S., Prins, G.|Journal of Investigative Medicine recent issues|Labels: prostate cancer

Estrogens are implicated in prostate development and cancer, while stem cells are essential in tissue homeostasis and carcinogenesis. We have previously demonstrated that estradiol-17β (E2) treatment augments prostaspheres (PS) number and size, implicating them as direct estrogen targets. The present studies sought to elucidate specific roles for ERα and ERβ in prostate stem and progenitor cells.

Prostate stem-progenitor cells were identified and isolated from normal primary prostate epithelial cells (PrEC) using long term BrdU retention in 3-D PS culture. FACS analyses (BrdU/ERα or ERβ) showed prostate stem and progenitor populations were both ERα+ and ERβ+. BrdU-retaining stem cells expressed high levels of ERβ and lower ERα as compared to non-label-retaining progenitor cells, suggesting ERβ dominance in the prostate stem cell. Estradiol increased BrdU-retaining cell numbers by enhancing stem cell self-renewal through symmetric division. While ERα siRNA blocked the E2-stimulated BrdU-retaining cells, ERβ knockdown augmented the E2-induced increase of BrdU-retaining cells. Together these findings suggest that ERα stimulates whereas ERβ suppresses stem cell self-renew. This conclusion is supported by separate studies on 2-D cultured PrEC with FACS stem-like cell side-population analysis using selective ER antagonists and siRNA. Although ERβ siRNA did not influence ERα mRNA levels, ERα siRNA doubled ERβ expression suggesting a suppressive role of ERα on ERβ action.

In total, the present findings identify distinct localization patterns and roles for ERα and ERβ in human prostate stem-like and daughter progenitor cells with ERα driving self-renewal and ERβ braking division. We propose that a delicate balance between ERα and ERβ contributes to prostate stem cell niche homeostasis and that their dysregulation may contribute to prostate carcinogenesis and progression.

Sunday, March 20, 2016 10:47 PM|Oncotarget|MedWorm: Cancer Therapy|Comments|Labels: prostate cancer
In this study, we first investigated the implication of the NPM1 and its Thr199 and Thr234/237 phosphorylated forms in PCa. We showed that phosphorylated forms of NPM1 interact with androgen receptor (AR) in nucleoplasm. N6L treatment of prostate tumor cells led to inhibition of NPM1 phosphorylation in conjunction with inhibition of AR activity. We also found that total and phosphorylated NPM1 were overexpressed in castration-resistant PCa. Assessment of the potential therapeutic role of N6L in PCa indicated that N6L inhibited tumor growth both in vitro and in vivo when used either alone or in combination with the standard-of-care first- (hormonotherapy) and second-line (docetaxel) treatments for advanced PCa. Our findings reveal the role of Thr199 and Thr234/237 phosphorylated NPM1 in PCa...
Thursday, March 10, 2016 4:00 PM|Cancer|Cancer via|Comments|Labels: prostate cancer
CONCLUSIONSThe use of proton therapy to treat patients with prostate cancer more than doubled from 2004 to 2012, with striking racial disparities in its use noted despite robust multivariable adjustments. Long‐term follow‐up is needed to determine whether the increased use of proton therapy for prostate cancer is justified, and ongoing efforts should be made to ensure equal access to resource‐limited oncologic therapies. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Wednesday, February 17, 2016 7:36 AM|Expert Review of Anticancer Therapy|MedWorm: Cancer Therapy|Comments|Labels: prostate cancer
Authors: Graff JN, Beer TM Abstract Three randomized studies examining docetaxel early in metastatic prostate cancer were recently reported. The CHAARTED and STAMPEDE studies showed a survival benefit for docetaxel when started with androgen suppression therapy in men with newly diagnosed metastatic prostate cancer. The STAMPEDE study also included men with biochemically relapsed prostate cancer. The benefit was a median of 13.6 months in the CHAARTED study and 10 months in STAMPEDE. The survival benefit in CHAARTED was stronger in those with high volume disease. The benefit in STAMPEDE was greater in metastatic, rather than biochemically relapsed, prostate cancer. The third study, GETUG-AFU 15, was a smaller study without a survival benefit. These data have changed how we treat me...
CONCLUSION: According to these results, the novel nanomedicine offers great promise for the dual drugs delivery to the prostate cancer cells, showing the potential of synergistic combination therapy for prostate cancer. PMID: 26203689 [PubMed - as supplied by publisher] (Source: Drug Delivery)

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Saturday, January 23, 2016 4:00 PM|Journal of Applied Biomedicine|MedWorm: Cancer Therapy|Comments|Labels: ROS, prostate cancer
Publication date: Available online 23 January 2016 Source:Journal of Applied Biomedicine Author(s): Valliappan Karuppiah, Kumarappan Alagappan, Kannan Sivakumar, Lakshmanan Kannan Phenazine-1-carboxylic acid has extensive pharmacological activity, including antibiotic and immunomodulatory, but the anticancer activity remains unknown. Treatment of prostate cancer cell line (DU145) with phenazine-1-carboxylic acid stimulated inhibition of cell proliferation in concentration- and time-dependent manner. Dual staining confirmed phenazine-1-carboxylic acid stimulated prostate cancer cell apoptosis in time-dependent manner. To investigate the exact mechanism, phenazine-1-carboxylic acid-stimulated oxidative stress and mitochondrial-related apoptotic pathway in human prostate cancer cells we...
Wednesday, January 13, 2016 4:00 PM|Cancer Research|MedWorm: Cancer Therapy|Comments|Labels: prostate cancer
Conclusions: There is no approved drug that can specifically target AR- independent NEPC tumors. The restricted set of therapeutic options against this subtype of prostate cancer and consequent dismal outcome stem in part from our incomplete understanding of the molecular events underlying its pathogenesis. The discovery that epigenetics can be a key process in distinguishing tumors that are AR-independent and at high risk for NEPC progression represents an important step to highlight the use of epigenetic modifiers as therapeutic agents for this subtype of prostate cancer.Citation Format: Loredana Puca, Dong Gao, Myriam Kossai, Joanna Cyrta, Clarisse Marotz, Juan Miguel Mosquera, Theresa Y. MacDonald, Andrea Sboner, Rema Rao, Yu Chen, Mark A. Rubin, Himisha Beltran. Targeting androgen-ind...
Monday, January 11, 2016 4:00 PM|Journal of Hematology and Oncology|MedWorm: Cancer Therapy|Comments|Labels: prostate cancer
Conclusions: The histone H2B of DU-145 prostate cancer cells are hypoacetylated, hypomethylated, and dephosphorylated. Histone deacetylase inhibitor reversed this phenotype. Epigenetic agent may therefore be useful for prostate cancer therapy and worth further investigation. (Source: Journal of Hematology and Oncology)
Thursday, January 7, 2016 7:28 AM|MedPage Today Urology|MedWorm: Cancer Therapy|Comments|Labels: prostate cancer, biomarker diagnostic
(MedPage Today) -- Tumor cell make-up predicts response to hormonal agents (Source: MedPage Today Urology)
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Cancer Therapy|Comments|Labels: AR, prostate cancer
Recurrence with lethal castration-resistant prostate cancer after androgen deprivation therapy remains the major challenge in treatment of advanced prostate cancer. Significant advances in our understanding of continued androgen receptor (AR) signaling in castration-resistant prostate cancer have led to the development and FDA approval of two next-generation androgen-directed therapies, the androgen biosynthesis inhibitor abiraterone and the potent AR antagonist enzalutamide. These drugs heralded a new era of prostate cancer therapy. However, some patients present with therapy-resistant disease, and most initial responders develop acquired resistance within months of therapy initiation. The resistance is typically accompanied by increased prostate-specific antigen, indicating reactivated A...
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: STAT, prostate cancer
Signal Transducer and Activator of Transcription 3 (STAT3) is constitutively activated in many cancer cell lines, leading to survival, proliferation, angiogenesis and metastasis. The inhibition of STAT3 by natural or synthetic compounds has been shown to sensitise cancer cell lines to the chemotherapy agent cisplatin, however the molecular mechanisms contributing to this chemosensitisation have not yet been fully elucidated. Therefore we investigated the effect of STAT3 inhibition on cisplatin-induced DNA damage and key DNA repair factors.STAT3 inhibitors stattic and curcumin were investigated in combination with cisplatin using the Suphorhodamine B cell growth inhibition assay in the DU145 prostate cancer and A549 non-small cell lung cancer cell lines. Combination treatments result in a s...
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Cancer Therapy|Comments|Labels: mTOR, prostate cancer
The mTOR pathway is frequently over-activated in human cancers. However, classic allosteric mTOR inhibitors rapamycin and its analogs only exert limited clinical benefits in patients. It has been shown that many tumors either fail to respond to rapamycin initially or are able to acquire resistance after the initial treatment of rapamycin. Such primary and secondary resistances remain as major concerns in rapamycin-based anti-cancer therapies that may inevitably lead to therapeutic failure. We have previously shown that the ATP-competitive dual mTOR kinase inhibitor AZD8055 can significantly inhibit malignant behaviors in parental cells however its functional efficacies in the rapamycin-resistance setting remains unclear.Cancer cells with wildtype PTEN were selected as models of primary rap...
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Cancer Therapy|Comments|Labels: MET, VEGF, prostate cancer, clinical trial
Several kinase inhibitors targeting aberrant signaling pathways in tumor cells have been deployed in cancer therapy. However, their impact on the tumor immune microenvironment remains poorly understood. The tyrosine kinase inhibitor cabozantinib showed striking responses in early phase clinical trials, particularly in cancer patients with bone metastases. Here we show that cabozantinib rapidly eradicates invasive, poorly-differentiated PTEN/p53 deficient murine prostate cancer. This was associated with increased neutrophil chemotactic factor expression, including CXCL12 and HMGB1 production by tumor cells, and robust infiltration of neutrophils into the tumor. Critically, cabozantinib-induced tumor clearance in mice was abolished by antibody-mediated granulocyte depletion or HMGB1 neutrali...
Sunday, January 3, 2016 4:00 PM|Current Cancer Drug Targets|MedWorm: Cancer Therapy|Comments|Labels: MET, prostate cancer
Authors: Xie Y, Istayeva S, Chen Z, Tokay T, Zhumadilov Z, Wu D, Hortelano G, Zhang J Abstract Membranous Met is classically identified with its role in cancer metastases, while nuclear Met is associated with a more invasive, aggressive and proliferative form of cancer. Full-length Met or N-terminal transmembrane domain cleaved Met can translocate into nucleus in a cell growth and pH dependent but ligand-dependent (full length Met) and -independent (cleaved Met) manner. nMET may play greater essential roles in cancer recurrence than membranous Met. For example in prostate cancer, it has been found that androgen receptor (AR) may inhibit the expression of membranous Met so anti-androgen based prostate cancer therapy may promote the expression of nuclear Met (nMET). We recently found...