Oncology Intelligence

Heat Shock Proteins HSP(7)

HSP90 is a chaperone that facilitates proper folding of specific client proteins in an ATP-dependent manner, has a role in buffering genetic variation, and stabilizes viral kinases and mutated oncoproteins, such as v-SRC and Bcr-Abl. HSPs that identify misfolded or unfolded proteins and target them for proteasomal degradation. Hsp70 binds exposed hydrophobic patches on the surface of misfolded proteins and recruits E3 ubiquitin ligases such as CHIP to tag the proteins for proteasomal degradation.(1, 2) Hsp27 and Hsp90 have been implicated in increasing the activity of the ubiquitin-proteasome system, though they are not direct participants in the process.(1) Mutant forms of EGFR, probably due to their constitutively-active kinases, are dependent on the chaperoning function of HSP90 through direct interaction.(3)
Vimentin, Hsp27, annexin IV, and serum amyloid -1 have been identified as reliable markers of RCC that are potentially useful in the clinical setting.(4) Hsp90 plays a role in facilitating transformation by stabilizing the mutated and overexpressed oncoproteins found in breast tumors, and permitting the activation of growth stimulatory and transforming pathways in the absence of growth factors. Hsp27 inhibits treatment-induced apoptosis and causes treatment resistance in PC and other cancers. Targeted suppression of Hsp27 sensitizes cancer cells to hormone and chemotherapy.(6) Unlike the other HSPs, Hsp27 does not bind ATP.(5)

Trial Drugs/Interactions
Generic Code Old Code Brand Company Indication trials
apatorsen OGX-427 OncoGenex P3: bladder: P2: NSCLC, SCLC, pancreatic, PC; P1: solid trials
ganetespib STA-9090 Synta P3: NSCLC; P2/3: BC; P2: CRC, AML, CML, MDS, ALL, melanoma, SCLC, pancreatic, PC, esophageal, GIST; P1/2: ovarian, fallopean; P1: adenocarcinoma, solid, hem trials
vitespen HSPPC-96 Oncophage Agenus P3: RCC (terminated), melanoma (2002); P2: CNS, GBM (2013), NSCLC, lung, sarcoma, lymphoma; P1: pancreatic trials
ritonavir Abbott P2: brain, astrocytoma, Kaposi's; P1/2: BC trials
AT13387 Astex P2: PC, NSCLC, GIST; P1: solid trials
AUY922 Novartis P2: GIST, NSCLC, lung, pancreatic, myeloproliferative, lymphoma, pancreatic, BC; P1/2: solid, MM; P1: stomach, esophageal, CRC trials
BIIB021 CNF2024 Biogen Idec P2: gastric, BC (2009); P1: solid, lymphoma, CLL trials
Debio 0932 Debiopharm P2: NSCLC; P1: RCC, solid, lymphoma trials
HSP70 vaccine noncorporate P1/2: BC; P1: leukemia, CML trials
SNX-5422 Esanex P1/2: solid; P1: hem, lymphoma, CLL trials
DS-2248 Daiichi Sankyo P1: solid, NSCLC trials
PU-H71 Tocris P1: solid, lymphoma trials
XL888 Exelixis P1: melanoma (2012), solid (terminated) trials
Failed Drugs
Generic Code Old Code Brand Company Indication trials
alvespimycin 17-DMAG KOS-1022 BMS terminated; P2: BC; P1: lymphoma, leukemia, oral, nasal, solid, small intestine trials
brivudine RP101 NB1011 Zostex Santa Cruz Last new trial started in 2007; P2: pancreatic; P1/2: CRC, solid trials
retaspimycin IPI-504 Infinity terminated; P3: GIST; P2: NSCLC, PC, melanoma, liposarcoma, BC; P1: MM, solid trials
tanespimycin 17-AAG KOS-953, CNF1010 BMS development halted; P3: gastric, MM; P2: pancreatic, RCC, BC, gynecological, leukemia, lymphoma, melanoma, PC, thyroid, HHL; P1/2: solid; P1: CLL, bladder, CRC, CML trials
ABI-010 Abraxis withdrawn; P1: solid trials
AG-858 Pfizer terminated; P2: CML trials
BIIB028 Biogen Idec Last new trial started in 2008; P1: solid trials
HSP990 Novartis terminated; P1: solid trials
ING-1 XOMA Last trial started in 2002; P1: Adenocarcinoma trials
IPI-493 Infinity terminated; P1: solid, hematologic trials
SGN-00101 Seattle Genetics Last new trial started in 2004; P2: cervical; P1/2: anal trials
MPC-3100 Myriad Last new trial started 2009; P1: various trials


1. Park S-H, Bolender N, Eisele F, Kostova Z, Takeuchi J, Coffino P, et al. The cytoplasmic Hsp70 chaperone machinery subjects misfolded and endoplasmic reticulum import-incompetent proteins to degradation via the ubiquitin-proteasome system. Molecular biology of the cell. 2007;18(1):153-65.

2. Proteosome. [cited]; Available from:

3. Pines G KW, Yarden Y. Oncogenic mutant forms of EGFR: lessons in signal transduction and targets for cancer therapy. FEBS Lett. 2010;584(12):2699-706. PMCID: 20388509.

4. Zacchia M VA, Capasso A, Morelli F, De Vita F, Capasso G. Genomic and proteomic approaches to renal cell carcinoma. J Nephrol. 2011;24(2):155-64. PMCID: 20437403.

5. Golubovskaya VM. Focal adhesion kinase as a cancer therapy target. Anti-cancer agents in medicinal chemistry. 2010;10(10):735.

6. M Kumano ea. Cotargeting Stress-Activated Hsp27 and Autophagy as a Combinatorial Strategy to Amplify Endoplasmic Reticular Stress in Prostate Cancer Mol Cancer Ther. 2012;11:1661.

7. Luo G-R, Chen S, Le W-D. Are heat shock proteins therapeutic target for Parkinson's disease? International journal of biological sciences. 2007;3(1):20.

Monday, September 19, 2016 7:24 AM|Ben Fidler|MIT Biotech Group - Essential Biotech RSS Feed|Labels: HSP, financial

Earlier this year, Blend Therapeutics changed its name to Tarveda Therapeutics and spun what used to be its lead drug into a separate company, the latest steps in a strategic overhaul. The wheeling and dealing continued this morning for the Watertown, MA, company, which has cut a deal with Madrigal Pharmaceuticals—the firm that recently merged with now-defunct Synta Pharmaceuticals—to add another potential cancer drug to the mix.

Tarveda has agreed to pay Madrigal (NASDAQ: MDGL) as much as $163 million overall—including an unspecified upfront payment—for the rights to a drug called PEN-866 and potentially others like it. Much of that cash will be tied to the progress of PEN-866, an experimental cancer drug that, like Tarveda’s other experimental therapies, is composed of two chemically linked molecules.

Tarveda drugs, which it calls pentarins, are essentially tinier versions of antibody-drug conjugates, or ADCs, a type of cancer treatment that links antibodies to toxins to attack tumors. The difference is pentarins use peptides—much smaller molecules than antibodies—to shepherd the drug to tumor cells, which in theory might help them penetrate tumor tissue more easily than ADCs. Tarveda’s lead drug, known as PEN-221, binds to a protein on the surface of neuroendocrine cells called somatostatin receptor 2, carrying the chemotherapy drug DM1. It’s supposed to begin clinical testing this year.

Through the Madrigal deal, Tarveda now has a second experimental drug, PEN-866. The drug targets heat shock protein 90 (HSP90), a so-called chaperone protein that helps shuttle other proteins around—including some that cause cancer—inside cells. HSP90 has been a popular cancer drug target, but drugs that block the protein haven’t fared well. Novartis’ AUY922, Infinity Pharmaceuticals’ (NASDAQ: INFI) IPI-504, and Synta’s ganetespib are just a few examples of companies whose HSP90-blocking drugs have failed. (Check out this article in the journal Clinical Advances in Hematology & Oncology for more on the history of HSP90 inhibitors).

The failure of ganetespib is what doomed Synta, a Lexington, MA, company that in April merged with Madrigal following a strategic review. The surviving company, which kept the Madrigal name, is focused on cardiovascular and liver diseases and trying to shed all of Synta’s cancer drug work. This includes Synta’s intellectual property on HSP90, which has led to what Tarveda is carrying forward as PEN-866. Tarveda says PEN-866 is different than past failed HSP90 inhibitors because it’s a conjugate—it doesn’t just block HSP90, it carries a byproduct of the toxic chemotherapy irinotecan. That’ll have to be proven in clinical trials, however; the first human study of PEN-866 should begin early next year.

Tarveda CEO Drew Fromkin called PEN-866 an “ideal fit” for the company, which is trying to prove that pentarins can overcome some of the limitations of ADCs and other cancer drugs. Fromkin took over the company last year, when it was still called Blend and focused on a few disparate methods of developing cancer drugs. Since that time, Blend has spun out its old lead drug, a next-gen platinum-based chemotherapy drug called BTP-114, into a new company called Placon Therapeutics and sharpened its focus on pentarins. Blend changed its name to Tarveda in January.

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Friday, September 16, 2016 4:27 PM|Hak-Bong Kim, Su-Hoon Lee, Jee-Hyun Um, Mi-Ju Kim, Suh-Kyung Hyun, Eun-Ji Gong, Won Keun Oh, Chi-Dug Kang, Sun-Hee Kim|International Journal of Biological Sciences|Labels: HSP, CML

Development of effective therapeutic strategies to eliminate cancer stem-like cells (CSCs), which play a major role in drug resistance and disease recurrence, is critical to improve cancer treatment outcomes. The current investigation was undertaken to examine the effectiveness of the combination treatment of Hsp90 inhibitor and SIRT1 inhibitor in inhibiting the growth of chemo-resistant stem-like cells isolated from human chronic myeloid leukemia K562 cells. Inhibition of SIRT1 by use of SIRT1 siRNA or SIRT1 inhibitors (amurensin G and EX527) effectively potentiated sensitivity of Hsp90 inhibitors (17-AAG and AUY922) in CD44high K562 stem-like cells expressing high levels of CSC-related molecules including Oct4, CD34, β-catenin, c-Myc, mutant p53 (mut p53), BCRP and P-glycoprotein (P-gp) as well as CD44. SIRT1 depletion caused significant down-regulation of heat shock factor 1 (HSF1)/heat shock proteins (Hsps) as well as these CSC-related molecules, which led to the sensitization of CD44high K562 cells to Hsp90 inhibitor by SIRT1 inhibitor. Moreover, 17-AAG-mediated activation of HSF1/Hsps and P-gp-mediated efflux, major causes of Hsp90 inhibitor resistance, was suppressed by SIRT1 inhibitor in K562-CD44high cells. Our data suggest that combined treatment with Hsp90 inhibitor and SIRT1 inhibitor could be an effective therapeutic approach to target CSCs that are resistant to current therapies.

Friday, September 16, 2016 4:27 PM|Yurong Zhang, Xuemei Tao, Guangzhi Jin, Haojie Jin, Ning Wang, Fangyuan Hu, Qin Luo, Huiqun Shu, Fangyu Zhao, Ming Yao, Jingyuan Fang, Wenming Cong, Wenxin Qin, Cun Wang|Theranostics|Labels: HSP, liver cancer

Heat shock protein 27 (Hsp27) is an ATP-independent molecular chaperone and confers survival advantages and resistance to cancer cells under stress conditions. The effects and molecular mechanisms of Hsp27 in HCC invasion and metastasis are still unclear. In this study, hepatocellular carcinoma (HCC) tissue array (n = 167) was used to investigate the expression and prognostic relevance of Hsp27 in HCC patients. HCC patients with high expression of Hsp27 exhibited poor prognosis. Overexpression of Hsp27 led to the forced invasion of HCC cells, whereas silencing Hsp27 attenuated invasion and metastasis of HCC cells in vitro and in vivo. We revealed that Hsp27 activated Akt signaling, which in turn promoted MMP2 and ITGA7 expression and HCC metastasis. We further observed that targeting Hsp27 using OGX-427 obviously suppressed HCC metastasis in two metastatic models. These findings indicate that Hsp27 is a useful predictive factor for prognosis of HCC and it facilitates HCC metastasis through Akt signaling. Targeting Hsp27 with OGX-427 may represent an attractive therapeutic option for suppressing HCC metastasis.

Thursday, September 15, 2016 11:42 PM|Eui Young So, Toru Ouchi|International Journal of Biological Sciences|Labels: HSP

Toll-like receptor (TLR) proteins play key roles in immune responses against infection. Using TLR proteins, host can recognize the conserved molecular structures found in pathogens called pathogen-associated molecular patterns (PAMPs). At the same time, some TLRs are able to detect specific host molecules, such as high-mobility group box protein 1 (HMGB1) and heat shock proteins (hsp), and lead to inflammatory responses. Thus, it has been suggested that TLRs are involved in the development of many pathogenic conditions. Recent advances in TLR-related research not only provide us with scientific information, but also show the therapeutic potential against diseases, such as autoimmune disease and cancer. In this mini review, we demonstrate how TLRs pathways could be involved in cancer development and their therapeutic application, and discuss recent patentable subjects, in particular, that are targeting this unique pathway.

Thursday, September 15, 2016 7:51 PM|Zongguo Yang, Liping Zhuang, Peter Szatmary, Li Wen, Hua Sun, Yunfei Lu, Qingnian Xu, Xiaorong Chen|International Journal of Medical Sciences|Labels: HSP, liver cancer

Background: Heat shock proteins (HSPs) are overexpressed in human hepatocellular carcinoma (HCC) tissue and correlate with aggressiveness and prognosis of HCC.

Methods: Using the GSE14520 microarray expression profile from Gene Expression Omnibus, we compared HSP gene expression between tumour and non-tumour tissues and correlated this with outcomes in HCC patients.

Results: We analysed 220 hepatitis B virus (HBV)-related HCC patients and 25 HSPs in this study. With the exception of HSPA4L, HSPA12A and HSPB8, members of the HSP family, including HSPH1, HSPBP1, HSPA1A, HSPA1B, HSPA1L, HSPA2, HSPA4, HSPA5, HSPA8, HSPA9, HSPAA1, HSPAB1, HSPA14, HSPB11, HSPA13, HSP90B1 and HSPBAP1, were all overexpressed in tumour tissues (all P < 0.001). In contrast, HSPB6, HSPB7, HSPA6, HSPB2 and HSPB3 were upregulated in non-tumour tissues (all P < 0.001). Multivariate analysis showed that cirrhosis (HR = 5.282, 95% CI = 1.294-21.555, P = 0.02), Barcelona Clinic liver cancer (BCLC) staging (HR = 2.151, 95% CI = 1.682-2.750, P < 0.001), HSPA12A (HR = 1.042, 95% CI = 1.003-1.082, P = 0.033) and HSP90B1 (HR = 1.001, 95% CI = 1.000-1.001, P = 0.011) were negatively associated with survival of HBV-related HCC patients. Furthermore, advanced BCLC staging (HR = 1.797, 95% CI = 1.439-2.244, P < 0.001) was also associated with earlier recurrence of HCC. The high expression of HSPA4 (HR = 1.002, 95% CI = 1.000-1.004, P = 0.019), HSPA5 (HR = 1.0, 95% CI = 1.0-1.0, P = 0.046) and HSPA6 (HR = 1.008, 95% CI = 1.001-1.015, P = 0.021) was similarly associated with HCC recurrence.

Conclusions: The expression of most HSPs was higher in tumour tissues than in non-tumour tissues. High BCLC staging scores, advanced cirrhosis and the overexpression of HSPA12A and HSP90B1 might be associated with poor survival from HCC, whereas high levels of HSPA4, HSPA5 and HSPA6 might be associated with earlier recurrence of HCC.

Friday, September 2, 2016 6:35 AM|Gaponova, A. V., Nikonova, A. S., Deneka, A. Y., Kopp, M. C., Kudinov, A. E., Skobeleva, N., Khazak, V., Ogawa, L. S., Cai, K. Q., Duncan, K. E., Duncan, J. S., Egleston, B. L., Proia, D. A., Boumber, Y., Golemis, E. A.|Clinical Cancer Research Online First Articles|Labels: HSP, lung cancer

Purpose: Small cell lung cancer (SCLC) is a highly aggressive disease representing 12% to 13% of total lung cancers, with median survival of <2 years. No targeted therapies have proven effective in SCLC. Although most patients respond initially to cytotoxic chemotherapies, resistance rapidly emerges, response to second-line agents is limited, and dose-limiting toxicities (DLT) are a major issue. This study performs preclinical evaluation of a new compound, STA-8666, in SCLC.

Experimental Design: To avoid DLT for useful cytotoxic agents, the recently developed drug STA-8666 combines a chemical moiety targeting active HSP90 (concentrated in tumors) fused via cleavable linker to SN38, the active metabolite of irinotecan. We compare potency and mechanism of action of STA-8666 and irinotecan in vitro and in vivo.

Results: In two SCLC xenograft and patient-derived xenograft models, STA-8666 was tolerated without side effects up to 150 mg/kg. At this dose, STA-8666 controlled or eliminated established tumors whether used in a first-line setting or in tumors that had progressed following treatment on standard first- and second-line agents for SCLC. At 50 mg/kg, STA-8666 strongly enhanced the action of carboplatin. Pharmacokinetic profiling confirmed durable STA-8666 exposure in tumors compared with irinotecan. STA-8666 induced a more rapid, robust, and stable induction of cell-cycle arrest, expression of signaling proteins associated with DNA damage and cell-cycle checkpoints, and apoptosis in vitro and in vivo, in comparison with irinotecan.

Conclusions: Together, these results strongly support clinical development of STA-8666 for use in the first- or second-line setting for SCLC. Clin Cancer Res; 1–10. ©2016 AACR.

Thursday, September 1, 2016 10:05 PM|Chen, L., Li, J., Farah, E., Sarkar, S., Ahmad, N., Gupta, S., Larner, J., Liu, X.|Molecular Cancer Therapeutics current issue|Labels: HSP, prostate cancer

Castration-resistant prostate cancer (CRPC) is the later stage of prostate cancer when the disease has stopped responding to androgen deprivation therapy (ADT). It has been established that androgen receptor (AR) reactivation is responsible for the recurrence of prostate cancer after ADT. Thus, targeting different pathways that regulate AR stability and activity should be a promising strategy for treatment of CRPC. Heat shock proteins (HSP) are chaperones that modify stability and activity of their client proteins. HSP90, a major player in the HSP family, regulates stability of many proteins, including AR and Polo-like kinase 1 (Plk1), a critical regulator of many cell-cycle events. Further, HSP90 is overexpressed in different cancers, including prostate cancer. Herein, we show that cotreatment of prostate cancer with AR antagonist enzalutamide and HSP90 inhibitor leads to more severe cell death due to a synergistic reduction of AR protein. Interestingly, we show that overexpression of Plk1 rescued the synergistic effect and that cotargeting HSP90 and Plk1 also leads to more severe cell death. Mechanistically, we show that E3 ligase CHIP, in addition to targeting AR, is responsible for the degradation of Plk1 as well. These findings suggest that cotargeting HSP90 and some of its client proteins may be a useful strategy in treatment of CRPC. Mol Cancer Ther; 15(9); 2107–18. ©2016 AACR.

Monday, July 11, 2016 6:40 AM|Elsevier|JournalTOCs API - Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (50 articles)|Labels: HSP, bladder cancer

Functional inhibition of Hsp70 by Pifithrin-μ switches Gambogic acid induced caspase dependent cell death to caspase independent cell death in human bladder cancer cells

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Vol. , No. (2016) pp. -
Publication date: Available online 7 July 2016 Source:Biochimica et Biophysica Acta (BBA) - Molecular Cell Research Author(s): Mohammad Ishaq, Rani Ojha, Kapil Sharma, Gaurav Sharma, Shrawan K. Singh, Sekhar Majumdar Heat shock protein-70kDa (Hsp70) is a member of molecular chaperone family, involved in the proper folding of various proteins. Hsp70 is important for tumor cell survival and is also reported to be involved in enhancing the drug resistance of various cancer types. Hsp70 controls apoptosis both upstream and downstream of the mitochondria by regulating the mitochondrial membrane permeabilization (MMP) and apoptosome formation respectively. In the present study, we have elucidated the role of Hsp70 in Gambogic acid (GA) induced apoptosis in bladder cancer cells. We observed that functional inhibition of Hsp70 by Pifithrin-μ switches GA induced caspase dependent (apoptotic) cell death to caspase independent cell death. However, this cell death was not essentially necrotic in nature, as shown by the observations like intact plasma membranes, cytochrome-c release and no significant effect on nuclear condensation/fragmentation. Inhibition of Hsp70 by Pifithrin-μ shows differential effect on MMP. GA induced MMP and cytochrome-c release was inhibited by Pifithrin-μ at 12h but enhanced at 24h. Pifithrin-μ also reverted back GA inhibited autophagy which resulted in the degradation of accumulated ubiquitinated proteins. Our results demonstrate that Hsp70 plays an important role in GA induced apoptosis by regulating caspase activation. Therefore, inhibition of Hsp70 may hamper with the caspase dependent apoptotic pathways induced by most anti-cancer drugs and reduce their efficacy. However, the combination therapy with Pifithrin-μ may be particularly useful in targeting apoptotic resistant cancer cells as Pifithrin-μ may initiate alternative cell death program in these resistant cells.

Monday, June 27, 2016 10:52 AM|ETO, D., HISAKA, T., HORIUCHI, H., UCHIDA, S., ISHIKAWA, H., KAWASHIMA, Y., KINUGASA, T., NAKASHIMA, O., YANO, H., OKUDA, K., AKAGI, Y.|Anticancer Research recent issues|Labels: HSP, liver cancer

Background/Aim: Heat-shock protein 27 (HSP27), a low molecular weight stress protein, is recognized as a molecular chaperone. The expression of HSP27 has been detected in some human tumors and while HSP27 is phosphorylated as a reresponse to stress, the function of phosphorylated HSP27 (p-HSP27) is not known. The aim of this study was to investigate what kind of effect expression of HSP27 and p-HSP27 in HCC has on clinicopathological characteristics and prognosis. Materials and Methods: An immunohistochemical study for HSP27 and p-HSP27 was performed on 194 resected HCC cases. We analyzed the correlation of HSP27 expression with various parameters statistically. Results: There was no correlation between expression of HSP27 and the clinicopathological characteristics and prognosis from the analysis of 194 cases. From the analysis of the hepatitis C virus (HCV)-positive group of 142 cases, those that were p-HSP27-positive had a larger tumor diameter and the portal vein invasion rate was high. Conclusion: The expression of total HSP27 may serve as a new, clinically useful marker of HCC. In addition, the present study suggests that the expression of phosphorylated HSP27 is useful in the screening and grading of HCC occurring in the setting of HCV.

Monday, June 27, 2016 10:52 AM|STOPE, M. B., WIEGANK, L., WEISS, M., DIESING, K., KOENSGEN, D., BURCHARDT, M., ZYGMUNT, M., MUSTEA, A.|Anticancer Research recent issues|Labels: HSP, ovarian cancer

Background: Heat-shock protein HSPB1 (alternative name HSP27) plays a pivotal role in cell survival pathways, apoptosis, metastasis and has been frequently linked to treatment resistance in ovarian cancer (OC) and other malignancies. Characteristic HSPB1 induction in different solid tumors is often caused by cytotoxic agents. Materials and Methods: An in vitro OC cell model system was established to characterize resistance mechanisms during chemotherapy. Human OC cell lines OVCAR-3, SK-OV-3 and TOV-21G were treated with paclitaxel or carboplatin. Cellular growth was analyzed by cell counting. Intra- and extracellular HSPB1 concentrations were assessed by western blot and enzyme-linked immunosorbent assays. Results: Incubation with paclitaxel, and with carboplatin significantly reduced cell growth without a definitive increase of intracellular HSPB1 expression. HSPB1 demonstrated drug-inducible secretion into the extracellular compartment. Conclusion: Despite its current lack of analysis in patient samples, serum soluble HSPB1 may function as a specific biomarker for monitoring response to chemotherapy in patients with OC.

Saturday, June 18, 2016 11:53 AM|Elsevier|JournalTOCs API - Trends in Biochemical Sciences (50 articles)|Labels: HSP

Clients Place Unique Functional Constraints on Hsp90

Trends in Biochemical Sciences, Vol. , No. (2016) pp. -
Publication date: Available online 10 June 2016 Source:Trends in Biochemical Sciences Author(s): Abbey D. Zuehlke, Len Neckers Heat shock protein 90 kDa (Hsp90) is required for the activation and stabilization of numerous client proteins, but the functional requirements of individual clients remain poorly understood. Utilizing yeast growth assays and mutational analysis, Mishra and colleagues explore the constraints placed on Hsp90 by distinct clients and the relationship between these constraints and overall yeast fitness.

Thursday, April 28, 2016 9:59 AM|SU, J.-M., HSU, Y.-Y., LIN, P., CHANG, H.|Anticancer Research recent issues|Labels: HSP, lung cancer

Background/Aim: Heat-shock protein 90 (HSP90) is a molecular chaperone that stabilizes many client proteins in normal and cancer cells, and approximately 3% of intracellular HSP90 is located in the nucleus. HSP90 is also targeted for the treatment of advanced non-small cell lung cancer (NSCLC). This study aimed to elucidate the clinical role of nuclear HSP90 levels in tissues from patients with NSCLC. Materials and Methods: Nuclear and total HSP90 levels were assessed using immunohistochemistry. Results: Multivariate logistic regression showed that the total HSP90 level was independently positively associated with age (p=0.041) and tumor histology of squamous type (p=0.007). By contrast, nuclear HSP90 level was independently positively associated with higher performance score (p=0.011), ever-smoking history (p=0.006) and presence of lymph node (p=0.036) or distant (p<0.001) metastasis, but not age or tumor histology. The level of nuclear HSP90, but not total HSP90, was negatively correlated with patient survival time (p<0.001). Conclusion: Nuclear accumulation of HSP90 might be a predictor of metastasis and survival in patients with NSCLC.

Monday, March 28, 2016 5:30 AM|Current Cancer Therapy Reviews|MedWorm: Cancer Therapy|Comments|Labels: HSP
The HSP response is implicated in conferring to breast and gynecologic malignancies different sensitivities to anticancer therapies including chemotherapy, endocrine therapy and immunotherapy (we are in the need of more studies about radiotherapy). The heat shock proteins are mainly implicated in cell death mechanisms, in cell differentiation including epithelial-mesenchymal transition, in tumor dormancy, in angiogenesis, metastasis formation, and in the escape of immunosurveillance. Considering the ample functions where the HSPs are implicated and that the HSP response is quite complex it is not surprising that the HSP response affects the anticancer therapies. Several of the HSPs have different predominant roles according to the molecular partners with which they interact, thus it is dif...

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Wednesday, March 23, 2016 4:00 PM|Thoracic Cancer|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: HSP
ConclusionsThe novel therapy of gefitinib combined with radiofrequency hyperthermia is safe and effective for advanced NSCLC patients. Whether an improvement in therapeutic efficacy is associated with the elevation of serum HSP70 concentration requires further study. (Source: Thoracic Cancer)
Tuesday, March 15, 2016 5:00 PM|Cancer Biology and Therapy|MedWorm: Cancer Therapy|Comments|Labels: HSP, liver cancer
Authors: Chettiar ST, Malek R, Annadanam A, Nugent KM, Kato Y, Wang H, Cades JA, Taparra K, Belcaid Z, Ballew M, Manmiller S, Proia D, Lim M, Anders RA, Herman JM, Tran PT Abstract Therapies for liver cancer particularly those including radiation are still inadequate. Inhibiting the stress response machinery is an appealing anti-cancer and radiosensitizing therapeutic strategy. Heat-shock-protein-90 (HSP90) is a molecular chaperone that is a prominent effector of the stress response machinery and is overexpressed in liver cancer cells. HSP90 client proteins include critical components of pathways implicated in liver cancer cell survival and radioresistance. The effects of a novel non-geldanamycin HSP90 inhibitor, ganetespib, combined with radiation were examined on three liver canc...
Monday, March 14, 2016 5:00 PM|Oncology (Williston Park, N.Y.)|MedWorm: Vaccines|Comments|Labels: HSP
Authors: Desjardins A, Vlahovic G, Friedman HS Abstract After years of active research and refinement, vaccine therapy and oncolytic viruses are becoming part of the arsenal in the treatment of gliomas. In contrast to standard treatment with radiation therapy and chemotherapy, vaccines are more specific to the patient and the tumor. The majority of ongoing vaccine trials are investigating peptide, heat shock protein, and dendritic cell vaccines. The immunosuppression triggered by the tumor itself and by its treatment is a major obstacle to vaccine and oncolytic virus therapy. Thus, combination therapy with different agents that affect the immune system will probably be necessary. PMID: 26984213 [PubMed - in process] (Source: Oncology (Williston Park, N.Y.))

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Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: HSP, RAS, lung cancer
Conclusion: The dual inhibition of HSP90 and MEK signaling pathways on sub-effective dose may constitute a potent therapeutic strategy to treat intrinsic MEK inhibitor resistant G13DKRAS mutant NSCLCs for resolving toxicity problem of dual inhibition of AKT and MEK in clinical trials.Citation Format: Dae Ho Lee, Kang-Seo Park, Bora Oh, Mi-Hee Lee, Hannah Yang. HSP90 inhibitor NVP-AUY922 sensitizes intrinsic MEK inhibitor Trametinib-resistant NSCLC cells harboring KRAS mutation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B90. (Source: Molecular Cancer Therapeutics)
Conclusions: TAS-116 administered once daily has an acceptable toxicity profile and the MTD was determined as 107.5 mg/m2. Preliminary antitumor activity was demonstrated with evidence of target engagement. The dose escalation study administered every other day is ongoing and the MTD will be determined.Clinical trial information: JapicCTI-142444.Citation Format: Akihiko Shimomura, Atsushi Horiike, Yuichi Tambo, Fumiyoshi Ohyanagi, Noriko Yanagitani, Satoru Kitazono, Yutaka Fujiwara, Yuko Tanabe, Shuichi Ohkubo, Noboru Yamamoto, Makoto Nishio. First-in-human phase I dose escalation study of TAS-116, a novel, orally active HSP90α and HSP90β selective inhibitor, in patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molec...