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Friday, September 16, 2016 4:27 PM|Zhenfeng Zhang, Pengfei Ma, Ying Jing, Ying Yan, Mei-Chun Cai, Meiying Zhang, Shengzhe Zhang, Huixin Peng, Zhi-Liang Ji, Wen Di, Zhenyu Gu, Wei-Qiang Gao, Guanglei Zhuang|Theranostics|Labels: ovarian cancer

Ovarian cancer is responsible for the highest mortality among all gynecologic malignancies, and novel therapies are urgently needed to improve patient outcome. Here we performed an integrative genomic analysis and identified the bromodomain and extraterminal domain (BET) protein BRD4 as a potential therapeutic target in ovarian cancer. Suppression of BRD4 using small-molecule BET inhibitors JQ1 and I-BET151, or dual kinase-bromodomain inhibitor volasertib, led to robust and broad antitumor effects across all subclasses of ovarian cancer. In contrast to many other cancers which are susceptible to BET inhibition due to downregulation of super-enhancer-dependent MYC transcript, we discovered that JQ1-sensitive ovarian cancer cells exhibited marked disruption of Forkhead box protein M1 (FoxM1) pathway, a key driver of ovarian carcinoma. These in vitro findings were further supported by in vivo efficacies of JQ1 targeting both cell line-based and patient-derived xenograft models. Our data establish a new treatment strategy against ovarian cancer by employing epigenetic vulnerabilities, and provide a mechanistic rationale for the clinical investigation of BET bromodomain inhibitors in this deadly disease.

Friday, September 16, 2016 3:40 AM| Obón-Santacana M, Lujan-Barroso L, Travis RC, Freisling H, Ferrari P, Severi G, Baglietto L, Boutron-Ruault MC, Fortner RT, Ose J, Boeing H, Menéndez V, Sánchez-Cantalejo E, Chamosa S, Castaño JM, Ardanaz E, Khaw KT, Wareham N, Merritt MA, Gunter MJ, Trichopoulou A, Papatesta EM, Klinaki E, Saieva C, Tagliabue G, Tumino R, Sacerdote C, Mattiello A, Bueno-de-Mesquita HB, Peeters PH, Onland-Moret NC, Idahl A, Lundin E, Weiderpass E, Vesper HW, Riboli E, Duell EJ|IARC Scientific Papers|Labels: ovarian cancer

Acrylamide and Glycidamide Hemoglobin Adducts and Epithelial Ovarian Cancer: A Nested Case-Control Study in Nonsmoking Postmenopausal Women from the EPIC Cohort.

Cancer Epidemiol Biomarkers Prev. 2016 Jan;25(1):127-34

Authors: Obón-Santacana M, Lujan-Barroso L, Travis RC, Freisling H, Ferrari P, Severi G, Baglietto L, Boutron-Ruault MC, Fortner RT, Ose J, Boeing H, Menéndez V, Sánchez-Cantalejo E, Chamosa S, Castaño JM, Ardanaz E, Khaw KT, Wareham N, Merritt MA, Gunter MJ, Trichopoulou A, Papatesta EM, Klinaki E, Saieva C, Tagliabue G, Tumino R, Sacerdote C, Mattiello A, Bueno-de-Mesquita HB, Peeters PH, Onland-Moret NC, Idahl A, Lundin E, Weiderpass E, Vesper HW, Riboli E, Duell EJ

Abstract
BACKGROUND: Acrylamide was classified as "probably carcinogenic to humans (group 2A)" by the International Agency for Research on Cancer. Epithelial ovarian cancer (EOC) is the fourth cause of cancer mortality in women. Five epidemiological studies have evaluated the association between EOC risk and dietary acrylamide intake assessed using food frequency questionnaires, and one nested case-control study evaluated hemoglobin adducts of acrylamide (HbAA) and its metabolite glycidamide (HbGA) and EOC risk; the results of these studies were inconsistent.
METHODS: A nested case-control study in nonsmoking postmenopausal women (334 cases, 417 controls) was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Unconditional logistic regression models were used to estimate ORs and 95% confidence intervals (CI) for the association between HbAA, HbGA, HbAA+HbGA, and HbGA/HbAA and EOC and invasive serous EOC risk.
RESULTS: No overall associations were observed between biomarkers of acrylamide exposure analyzed in quintiles and EOC risk; however, positive associations were observed between some middle quintiles of HbGA and HbAA+HbGA. Elevated but nonstatistically significant ORs for serous EOC were observed for HbGA and HbAA+HbGA (ORQ5vsQ1, 1.91; 95% CI, 0.96-3.81 and ORQ5vsQ1, 1.90; 95% CI, 0.94-3.83, respectively); however, no linear dose-response trends were observed.
CONCLUSION: This EPIC nested case-control study failed to observe a clear association between biomarkers of acrylamide exposure and the risk of EOC or invasive serous EOC.
IMPACT: It is unlikely that dietary acrylamide exposure increases ovarian cancer risk; however, additional studies with larger sample size should be performed to exclude any possible association with EOC risk. Cancer Epidemiol Biomarkers Prev; 25(1); 127-34. ©2015 AACR.

PMID: 26598536 [PubMed - in process]

Thursday, September 15, 2016 7:51 PM|Yu Bai, Maling Gou, Tao Yi, Li Yang, Lili Liu, Xiaojuan Lin, Dan Su, Yuquan Wei, Xia Zhao|International Journal of Medical Sciences|Labels: ovarian cancer

The use of toxins for cancer therapy has great promise. Gelonin, a potent plant toxin, causes cell death by inactivating the 60S ribosomal subunit. Recently, we developed a novel gene delivery system using biodegradable cationic heparin-polyethyleneimine (HPEI) nanogels. In the current study, the antitumor activity of a recombinant plasmid expressing gelonin (pGelonin) on human ovarian cancer was assessed. The application of HPEI nanogels, was also evaluated. Gelonin-cDNA was cloned into the pVAX1 plasmid vector and transfected into SKOV3 human ovarian cancer cells using biodegradable cationic HPEI nanogels. The expression of gelonin in vitro and in vivo was confirmed using RT-PCR and western blot analysis. Cell viability and apoptosis were examined using an MTT assay and flow cytometric analysis. For the in vivo study, an SKOV3 intraperitoneal ovarian carcinomatosis model was established, and nude mice were randomly assigned into four groups receiving i.p. administration of pGelonin/HPEI complexes, pVAX/HPEI complexes, HPEI alone and 5% glucose solution. The tumor weight was monitored, and a TUNEL assay and Ki-67 immunohistochemistry were performed to evaluate apoptosis and cell proliferation in the tumor tissue sections, respectively. Gelonin was efficiently expressed in SKOV3 cancer cells in vitro and in vivo using pGelonin incorporated with HPEI nanogels. The pGelonin/HPEI complexes inhibited cell viability and induced apoptosis in the cell culture. Treatment for intraperitoneal carcinomatosis with pGelonin/HPEI complexes reduced the tumor weight by ~58.55% compared to the control groups (P<0.05). The antitumor effect was accompanied by increased apoptosis and reduced cell proliferation (P<0.05). No significant side effects were observed with i.p. administration of the pGelonin/HPEI complexes. Our data indicate that HPEI nanogel-delivered pGelonin may have promising applications against human ovarian cancer.

Thursday, September 15, 2016 7:42 AM|Leonard, B., Starrett, G. J., Maurer, M. J., Oberg, A. L., Van Bockstal, M., Van Dorpe, J., De Wever, O., Helleman, J., Sieuwerts, A. M., Berns, E. M. J. J., Martens, J. W. M., Anderson, B. D., Brown, W. L., Kalli, K. R., Kaufmann, S. H., Harris, R. S.|Clinical Cancer Research current issue|Labels: ovarian cancer

Purpose: APOBEC3 DNA cytosine deaminase family members normally defend against viruses and transposons. However, deregulated APOBEC3 activity causes mutations in cancer. Because of broad expression profiles and varying mixtures of normal and cancer cells in tumors, including immune cell infiltration, it is difficult to determine where different APOBEC3s are expressed. Here, we ask whether correlations exist between APOBEC3 expression and T-cell infiltration in high-grade serous ovarian cancer (HGSOC), and assess whether these correlations have prognostic value.

Experimental Design: Transcripts for APOBEC3G, APOBEC3B, and the T-cell markers, CD3D, CD4, CD8A, GZMB, PRF1, and RNF128 were quantified by RT-qPCR for a cohort of 354 HGSOC patients. Expression values were correlated with each other and clinical parameters. Two additional cohorts were used to extend HGSOC clinical results. Immunoimaging was used to colocalize APOBEC3G and the T-cell marker CD3. TCGA data extended expression analyses to additional cancer types.

Results: A surprising positive correlation was found for expression of APOBEC3G and several T cell genes in HGSOC. Immunohistochemistry and immunofluorescent imaging showed protein colocalization in tumor-infiltrating T lymphocytes. High APOBEC3G expression correlated with improved outcomes in multiple HGSOC cohorts. TCGA data analyses revealed that expression of APOBEC3D and APOBEC3H also correlates with CD3D across multiple cancer types.

Conclusions: Our results identify APOBEC3G as a new candidate biomarker for tumor-infiltrating T lymphocytes and favorable prognoses for HGSOC. Our data also highlight the complexity of the tumor environment with respect to differential APOBEC family gene expression in both tumor and surrounding normal cell types. Clin Cancer Res; 22(18); 4746–55. ©2016 AACR.

Thursday, September 15, 2016 7:42 AM|Skates, S. J.|Clinical Cancer Research current issue|Labels: ovarian cancer

CA125 dominated performance for ovarian cancer early detection among four serum biomarkers evaluated in EPIC study prediagnostic serum, rising on average 3 years prior to detection. Adding HE4 provided only marginal improvement. This natural history supports annual testing for early detection and highlights the importance of biomarker discovery complementing CA125. Clin Cancer Res; 22(18); 4542–4. ©2016 AACR.

See related article by Terry et al., p. 4664

Thursday, September 15, 2016 7:42 AM|R. S.|JournalTOCs API - Clinical Cancer Research (27 articles)|Labels: ovarian cancer

High APOBEC3G Expression in TILs in Ovarian Cancer
Leonard, B Starrett, G. J, Maurer, M. J, Oberg, A. L, Van Bockstal, M, Van Dorpe, J, De Wever, O, Helleman, J, Sieuwerts, A. M, Berns, E. M. J. J, Martens, J. W. M, Anderson, B. D, Brown, W. L, Kalli, K. R, Kaufmann, S. H, Harris, R. S.
Clinical Cancer Research, Vol. 22, No. 18 (2016) pp. 4746 - 4755
Purpose: APOBEC3 DNA cytosine deaminase family members normally defend against viruses and transposons. However, deregulated APOBEC3 activity causes mutations in cancer. Because of broad expression profiles and varying mixtures of normal and cancer cells in tumors, including immune cell infiltration, it is difficult to determine where different APOBEC3s are expressed. Here, we ask whether correlations exist between APOBEC3 expression and T-cell infiltration in high-grade serous ovarian cancer (HGSOC), and assess whether these correlations have prognostic value. Experimental Design: Transcripts for APOBEC3G, APOBEC3B, and the T-cell markers, CD3D, CD4, CD8A, GZMB, PRF1, and RNF128 were quantified by RT-qPCR for a cohort of 354 HGSOC patients. Expression values were correlated with each other and clinical parameters. Two additional cohorts were used to extend HGSOC clinical results. Immunoimaging was used to colocalize APOBEC3G and the T-cell marker CD3. TCGA data extended expression analyses to additional cancer types. Results: A surprising positive correlation was found for expression of APOBEC3G and several T cell genes in HGSOC. Immunohistochemistry and immunofluorescent imaging showed protein colocalization in tumor-infiltrating T lymphocytes. High APOBEC3G expression correlated with improved outcomes in multiple HGSOC cohorts. TCGA data analyses revealed that expression of APOBEC3D and APOBEC3H also correlates with CD3D across multiple cancer types. Conclusions: Our results identify APOBEC3G as a new candidate biomarker for tumor-infiltrating T lymphocytes and favorable prognoses for HGSOC. Our data also highlight the complexity of the tumor environment with respect to differential APOBEC family gene expression in both tumor and surrounding normal cell types. Clin Cancer Res; 22(18); 4746&ndash;55. &copy;2016 AACR.

Thursday, September 15, 2016 7:42 AM|Schock, H, Fortner, R. T, Hüsing, A, Fichorova, R. N, Yamamoto, H. S, Vitonis, A. F, Johnson, T, Overvad, K, Tjonneland, A, Boutron-;Ruault, M.-;C, Mesrine, S, Severi, G, Dossus, L, Rinaldi, S, Boeing, H, Benetou, V, Lagiou, P, Trichopoulou, A, Krogh, V, Kuhn, E, Panico, S, Bueno-;de-;Mesquita, H. B, Onland-;Moret, N. C, Peeters, P. H, Gram, I. T, Weiderpass, E, Duell, E. J, Sanchez, M.-;J, Ardanaz, E, Etxezarreta, N, Navarro, C, Idahl, A, Lundin, E, Jirström, K, Manjer, J, Wareham, N. J, Khaw, K.-;T, Byrne, K. S, Travis, R. C, Gunter, M. J, Merritt, M. A, Riboli, E, Cramer, D. W, Kaaks, R.|JournalTOCs API - Clinical Cancer Research (27 articles)|Labels: ovarian cancer, biomarker diagnostic

Early Detection Biomarkers for Ovarian Cancer
Terry, K. L Schock, H, Fortner, R. T, Hüsing, A, Fichorova, R. N, Yamamoto, H. S, Vitonis, A. F, Johnson, T, Overvad, K, Tjonneland, A, Boutron-Ruault, M.-C, Mesrine, S, Severi, G, Dossus, L, Rinaldi, S, Boeing, H, Benetou, V, Lagiou, P, Trichopoulou, A, Krogh, V, Kuhn, E, Panico, S, Bueno-de-Mesquita, H. B, Onland-Moret, N. C, Peeters, P. H, Gram, I. T, Weiderpass, E, Duell, E. J, Sanchez, M.-J, Ardanaz, E, Etxezarreta, N, Navarro, C, Idahl, A, Lundin, E, Jirström, K, Manjer, J, Wareham, N. J, Khaw, K.-T, Byrne, K. S, Travis, R. C, Gunter, M. J, Merritt, M. A, Riboli, E, Cramer, D. W, Kaaks, R.
Clinical Cancer Research, Vol. 22, No. 18 (2016) pp. 4664 - 4675
Purpose: About 60% of ovarian cancers are diagnosed at late stage, when 5-year survival is less than 30% in contrast to 90% for local disease. This has prompted search for early detection biomarkers. For initial testing, specimens taken months or years before ovarian cancer diagnosis are the best source of information to evaluate early detection biomarkers. Here we evaluate the most promising ovarian cancer screening biomarkers in prospectively collected samples from the European Prospective Investigation into Cancer and Nutrition study. Experimental Design: We measured CA125, HE4, CA72.4, and CA15.3 in 810 invasive epithelial ovarian cancer cases and 1,939 controls. We calculated the sensitivity at 95% and 98% specificity as well as area under the receiver operator curve (C-statistic) for each marker individually and in combination. In addition, we evaluated marker performance by stage at diagnosis and time between blood draw and diagnosis. Results: We observed the best discrimination between cases and controls within 6 months of diagnosis for CA125 (C-statistic = 0.92), then HE4 (0.84), CA72.4 (0.77), and CA15.3 (0.73). Marker performance declined with longer time between blood draw and diagnosis and for earlier staged disease. However, assessment of discriminatory ability at early stage was limited by small numbers. Combinations of markers performed modestly, but significantly better than any single marker. Conclusions: CA125 remains the single best marker for the early detection of invasive epithelial ovarian cancer, but can be slightly improved by combining with other markers. Identifying novel markers for ovarian cancer will require studies including larger numbers of early-stage cases. Clin Cancer Res; 22(18); 4664&ndash;75. &copy;2016 AACR. See related commentary by Skates, p. 4542

Contributors : Minchul Kim ; Falong Lu ; Yi Zhang
Series Type : Expression profiling by high throughput sequencing ; Genome binding/occupancy profiling by high throughput sequencing
Organism : Homo sapiens

ARID1A is frequently mutated in ovarian clear-cell carcinoma (OCCC) and often co-exists with activating mutations of PIK3CA. Although induction of pro-inflammatory cytokines has been observed in this cancer, the mechanism by which the two mutations synergistically activate cytokine genes remains elusive. Here we established an in vitro model of OCCC by introducing ARID1A knock-down and mutant PIK3CA in a normal human ovarian epithelial cell line, which resulted in cell transformation and cytokine gene induction. We demonstrate that loss of ARID1A impairs the recruitment of the Sin3A-HDAC complex, while PIK3CA mutation releases RelA from IkB, leading to cytokine gene activation. We show that an NF-kB inhibitor partly attenuates proliferation of OCCC and improves the efficacy of carboplatin both in cell culture and a mouse model. Our study thus reveals the mechanistic link between ARID1A/PIK3CA mutations and cytokine gene induction in OCCC, and suggests NF-kB inhibition can be a potential therapeutic option.

Tuesday, September 13, 2016 11:38 PM|Masafumi Koshiyama, Noriomi Matsumura, Ikuo Konishi|Journal of Cancer|Labels: ovarian cancer

Various trials of ovarian cancer screening programs have been reported worldwide. In 2011, one of the most famous papers indicated that annual screening using CA125/transvaginal sonography (TVS) did not reduce ovarian cancer mortality in the United States of America (USA). To investigate the validity of ovarian cancer screening, we verified the analyses of previous reports. At first, we obtained the USA datasets that were used for the analyses and identified many patients in whom cancers were accidentally detected several years after the screening period. We thus performed a new prognostic comparison between the screening group (cancers that were detected through screening or within one year after screening) and the control group (cancers that were found more than one year after screening, without screening, or in the original control group). The results showed that the prognoses of the screening group were significantly better than those of the control group (p=0.0017). In addition, the screening group contained significantly fewer stage IV cases than the control group (p=0.005). In another screening in the United Kingdom, ovarian cancer was detected at a relatively earlier stage (stage I/II: 44%), while the rate of stage IV detection was low (4%). Very recently, this team showed significant difference in the rates with and without screening (p=0.021) when prevalent cases were excluded and indicated the delayed effect of screening. These results contrasted with the USA data. In other studies in the USA and Japan, annual screening was also associated with a decreased stage at detection. New histopathological, molecular and genetic studies have recently provided two categories of ovarian carcinogenesis. Type I carcinomas are slow-growing neoplasms that often develop from benign ovarian cysts. Type II carcinomas are high-grade clinically aggressive neoplasms. The rate of type II carcinomas is significantly higher in Europe and the USA than in Asia (p<0.001). Conversely, type I carcinomas are relatively common in Asia. These data theoretically imply that annual screening would be more effective in Asia.

Tuesday, September 13, 2016 11:38 PM|Radosław Januchowski, Monika Świerczewska, Karolina Sterzyńska, Karolina Wojtowicz, Michał Nowicki, Maciej Zabel|Journal of Cancer|Labels: ovarian cancer

Ovarian cancer is the most lethal gynaecological cancer. The main reason for the high mortality among ovarian cancer patients is the development of drug resistance. The expression of collagen genes by cancer cells can increase drug resistance by inhibiting the penetration of the drug into the cancer tissue as well as increase apoptosis resistance. In this study, we present data that shows differential expression levels of collagen genes and proteins in cisplatin- (CIS), paclitaxel- (PAC), doxorubicin- (DOX), topotecan- (TOP), vincristine- (VIN) and methotrexate- (MTX) resistant ovarian cancer cell lines. Quantitative real-time polymerase chain reactions were performed to determine the mRNA levels. Protein expression was detected using Western blot and immunocytochemistry assays. In the drug resistant cell lines, we observed the upregulation of eight collagen genes at the mRNA level and based on these expression levels, we divided the collagen genes into the following three groups:

1. Genes with less than a 50-fold increase in expression: COL1A1, COL5A2, COL12A1 and COL17A1. 2. Genes with greater than a 50-fold increase in expression: COL1A2, COL15A1 and COL21A1. 3. Gene with a very high level of expression: COL3A1. Expression of collagen (COL) proteins from groups 2 and 3 were also confirmed using immunocytochemistry. Western blot analysis showed very high expression levels of COL3A1 protein, and immunocytochemistry analysis showed the presence of extracellular COL3A1 in the W1TR cell line. The cells mainly responsible for the extracellular COL3A1 production are aldehyde dehydrogenase-1A1 (ALDH1A1) positive cells. All correlations between the types of cytostatic drugs and the expression levels of different COL genes were studied, and our results suggest that the expression of fibrillar collagens may be involved in the TOP and PAC resistance of the ovarian cancer cells. The expression pattern of COL genes provide a preliminary view into the role of these proteins in cytostatic drug resistance of cancer cells. The exact role of these COL genes in drug resistance requires further investigation.

Tuesday, September 13, 2016 11:38 PM|Lijun Fan, Mingzhu Yin, Chaofu Ke, Tingting Ge, Guangming Zhang, Wang Zhang, Xiaohua Zhou, Ge Lou, Kang Li|Journal of Cancer|Labels: ovarian cancer, biomarker diagnostic

The early detection of ovarian carcinoma is difficult due to the absence of recognizable physical symptoms and a lack of sensitive screening methods. The currently available biomarkers (such as CA125 and HE4) are insufficiently reliable to distinguish early stage (I/II) epithelial ovarian cancer (EOC) patients from normal individuals because they possess a relatively poor sensitivity and specificity. To evaluate the application of metabolomics to biomarker discovery in the early stages of epithelial ovarian cancer (EOC), plasma samples from 21 early stage EOC patients and 31 healthy controls were analyzed with ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC/Q-Tof/MS) in conjunction with multivariate statistical analysis. Eighteen metabolites, including lysophospholipids, 2-piperidone and MG (18:2), were found to be disturbed in early stage EOC with satisfactory diagnostic accuracy (AUC=0.920). These biomarkers were specifically validated in the EOC nude mouse model, and five of the biomarkers (lysophospholipids, adrenoyl ethanolamide et al.) were highly suspected of being associated with EOC because they were differentially expressed with the same tendency in the EOC nude mice versus normal controls. In conclusion, the selected metabolic biomarkers have considerable utility and significant potential for diagnosing early ovarian cancer and investigating its underlying mechanisms.

Tuesday, September 13, 2016 11:38 PM|Wei Huang, Quan Zhou, Xia Yuan, Ze-mei Ge, Fu-xiang Ran, Hua-yu Yang, Guang-liang Qiang, Run-tao Li, Jing-rong Cui|Journal of Cancer|Labels: Bcl-2, NFKb, STAT, ovarian cancer

Cisplatin is one of the most common drugs used for treatment of solid tumors such as ovarian cancer. Unfortunately, the development of resistance against this cytotoxic agent limits its clinical use. Here we report that YSY01A, a novel proteasome inhibitor, is capable of suppressing survival of cisplatin-resistant ovarian cancer cells by inducing apoptosis. And YSY01A treatment enhances the cytotoxicity of cisplatin in drug-resistant ovarian cancer cells. Specifically, YSY01A abrogates regulatory proteins important for cell proliferation and anti-apoptosis including NF-κB p65 and STAT3, resulting in down-regulation of Bcl-2. A dramatic increase in cisplatin uptake was also observed by inductively coupled plasma-mass spectrometry following exposure to YSY01A. Taken together, YSY01A serves as a potential candidate for further development as anticancer therapeutics targeting the proteasome.

Tuesday, September 13, 2016 11:38 PM|Min Zhao, Jiayi Wan, Ke Zeng, Mancy Tong, Arier C Lee, Jinxin Ding, Qi Chen|Journal of Cancer|Labels: ovarian cancer

Ovarian cancer is the third most common gynaecological malignancy. Changes in circadian rhythms such as bright light exposure may affect female reproductive physiology. Night shift work is associated with higher risks of developing gynaecological cancers. In addition, the season of birth is also suggested as an important environmental risk factor for developing gynaecological cancers. Melatonin may play an important role in this association as a marker of circadian rhythms. Serum from 96 women with ovarian cancer and 40 healthy women were collected and the level of melatonin was measured. In addition 277 women with ovarian cancer and 1076 controls were retrospectively collected for season of birth analysis over seven years. The serum levels of melatonin were significantly lower in women with ovarian cancer compared with healthy women (p<0.05). However there was no difference in melatonin levels in perimenopausal and postmenopausal patients. In addition, there is no statistically significant difference in seasonal distribution of birth between ovarian cancer patients and the control group. The melatonin levels in ovarian cancer patients and controls were not associated with the season of birth. Our results demonstrate the lower serum levels of melatonin in ovarian cancer patients which may contribute to the pathogenesis of ovarian cancer. The incidence of ovarian cancer was not associated with the season of birth. The serum levels of melatonin do not appear to be associated with season of birth in ovarian cancer patients.

Tuesday, September 13, 2016 11:38 PM|Christine Mayer, Silvia Darb-Esfahani, Anne-Sophie Meyer, Katrin Hübner, Joachim Rom, Christof Sohn, Ioana Braicu, Jalid Sehouli, G. Maria Hänsch, Matthias M. Gaida|Journal of Cancer|Labels: ovarian cancer

Background: Ovarian cancer (OvCa) is a highly aggressive malignoma with a tumor-promoting microenvironment. Infiltration of polymorphonuclear neutrophils (PMN) is frequently seen, raising the question of their impact on tumor development. In that context, effects of PMN on human ovarian cancer cells were assessed.

Methods: Human epithelial ovarian cancer cells were incubated with human PMN, lysate of PMN, or neutrophil elastase. Morphological alterations were observed by time-lapse video-microscopy, and the underlying molecular mechanism was analyzed by flow cytometry and Western blotting. Functional alternations were assessed by an in vitro wound healing assay. In parallel, a large cohort of n=334 primary OvCa tissue samples of various histological subtypes was histologically evaluated.

Results: Co-cultivation of cancer cells with either PMN or PMN lysate causes a change of the polygonal epithelial phenotype of the cells towards a spindle shaped morphology, causing a cribriform cell growth. The PMN-induced alteration could be attributed to elastase, a major protease of PMN. Elastase-induced shape change was most likely due to the degradation of membranous E-cadherin, which results in loss of cell contacts and polarity. Moreover, in response to elastase, epithelial cytokeratins were downmodulated, in parallel with a nuclear translocation of β-catenin. These PMN-elastase induced alterations of cells are compatible with an epithelial-to-mesenchymal transition (EMT) of the cancer cells. Following EMT, the cells displayed a more migratory phenotype. In human biopsies, neutrophil infiltration was seen in 72% of the cases. PMN infiltrates were detected preferentially in areas with low E-cadherin expression.

Conclusion: PMN in the microenvironment of OvCa can alter tumor cells towards a mesenchymal and migratory phenotype.

Tuesday, September 13, 2016 11:38 PM|Patrizia Vici, Laura Pizzuti, Luigi Di Lauro, Laura Conti, Chiara Mandoj, Anna Antenucci, Giovanna Digiesi, Domenico Sergi, Antonella Amodio, Paolo Marchetti, Francesca Sperati, Mario Valle, Alfredo Garofalo, Enrico Vizza, Giacomo Corrado, Cristina Vincenzoni, Federica Tomao, Ramy Kayal, Annalise Marsella, Mariantonia Carosi, Barbara Antoniani, Antonio Giordano, Marcello Maugeri-Saccà, Maddalena Barba|Journal of Cancer|Labels: ovarian cancer

Background: Over the last twenty years, the efforts of the scientific community devoted to the comprehension and treatment of ovarian cancer have remained poorly remunerative, with the case-fatality ratio of this disease remaining disappointedly high. Limited knowledge of the basic principles regulating ovarian carcinogenesis and factors impacting the course of disease may significantly impair our ability to intervene in early stages and lessen our expectations in terms of treatment outcomes. In the present study, we sought to assess whether metabolic factors and anthropometric indicators, i.e., pre-treatment fasting glucose and body mass index, are associated with renown cancer related prognostic factors such as tumour stage and grade at diagnosis.

Materials and Methods: Study participants were 147 women diagnosed with epithelial ovarian cancer and treated with platinum based regimens and/or surgery at the Regina Elena National Cancer Institute of Rome, Italy. Glucose levels were assessed at the institutional laboratories on venous blood collected in overnight fasting conditions and prior to any therapeutic procedure. Stage was coded according to the FIGO staging system based on the results of the diagnostic workup, while tumour grade was locally assessed by an expert pathologist. Participants' characteristics were descriptively analyzed for the overall study population and in a subgroup of 70 patients for whom data on body mass index (BMI) were available. FIGO stage and grade were compared by categories of pre-treatment fasting glucose defined upon the median value, i.e., 89 mg/dl. The association of interest was tested in regression models including BMI.

Results: For the overall study population, patients in the lowest category of fasting glucose were significantly more likely to exhibit a FIGO stage III-IV at diagnosis compared with their counterpart in the highest glucose category (81.3 vs 66.7%, p: 0.021). Subgroup analysis in 70 patients with BMI data confirmed this association (81.5 vs 55.8, p: 0.049), which remained significant when tested in regression models including BMI (OR: 0.28 95% CI 0.086-0.89, p: 0.031). No relevant evidence emerged when testing the association between fasting glucose and tumour grade.

Conclusions: In patients diagnosed with epithelial ovarian cancer, pre-treatment glucose levels appear to be inversely associated with FIGO stage. Further studies are warranted to eventually confirm and correctly interpret the implications of this novel finding.

Tuesday, September 13, 2016 11:38 PM|Laura H. Engelke, Alexandra Hamacher, Peter Proksch, Matthias U. Kassack|Journal of Cancer|Labels: EGFR, ROS, ovarian cancer

Purpose. Several studies have shown that natural compounds like resveratrol or ellagic acid have anticancer and antioxidant properties and can stimulate apoptosis in many cancer cell lines. The aim of this study was to elucidate if resveratrol or ellagic acid, respectively, could improve the efficacy of cisplatin in ovarian cancer.

Methods. As a cellular resistance model, the epithelial ovarian cancer cell line A2780 and its cisplatin-resistant subclone A2780CisR were used. A2780CisR was obtained by intermittent treatment of A2780 with cisplatin for 26 weekly cycles and showed a 4-6-fold increased resistance towards cisplatin compared to A2780.

Results. Pretreatment with resveratrol or ellagic acid 48 h prior to treatment with cisplatin showed a moderate enhancement of cisplatin cytotoxicity in A2780CisR cells (shift factors were 1.6 for ellagic acid and 2.5 for resveratrol). However, intermittent treatment of A2780 with cisplatin for 26 weekly cycles in permanent presence of resveratrol or ellagic acid, respectively, completely prevented the development of cisplatin resistance. The generated cell lines named A2780Resv and A2780Ellag displayed functional characteristics (migration, proliferation, apoptosis, activation of ErbB3, ROS generation) similar to the parental cell line A2780.

Conclusion. In conclusion, weekly intermittent treatment cycles of cisplatin-sensitive ovarian cancer cells with cisplatin retain cisplatin chemosensitivity in permanent presence of ellagic acid or resveratrol, respectively, whereas clinically relevant cisplatin chemoresistance develops in the absence of ellagic acid or resveratrol. Use of natural phenolic compounds may thus be a promising approach to prevent cisplatin resistance in ovarian cancer.

Tuesday, September 13, 2016 8:19 PM|Yanling Feng, Fan He, Huini Wu, He Huang, Lan Zhang, Xian Han, Jihong Liu|Journal of Cancer (RSS 2.0)|Labels: ovarian cancer

Objective: Golgi phosphoprotein 3 (GOLPH3) is a highly conserved membrane protein that is involved in a variety of cancers such as colorectal cancer, gastric cancer, ovarian cancer, and breast cancer. GOLPH3L is a paralog of GOLPH3. Although these proteins share a similar amino acid sequence, much less is known regarding the subcellular functions or effects of GOLPH3L on cancer compared with GOLPH3. The role of GOLPH3L in epithelial ovarian cancer (EOC) has not yet been investigated.

Methods: Using western blot, PCR and immunohistochemical analyses, we studied the clinical significance of GOLPH3L expression in EOC. The correlations between GOLPH3L expression and the clinicopathological variables of patients with EOC were assessed using Pearson's χ2 test. Kaplan-Meier analysis was used to compare the postoperative survival between groups of patients with EOC with varying levels of GOLPH3L expression.

Results: High expression of GOLPH3L was more frequently observed in EOC tissues than in corresponding adjacent non-tumor tissues. The expression of GOLPH3L correlated closely with pre-operative CA125 level (P=0.031). Univariate analysis showed that age, FIGO stage, pre-operative cancer antigen (CA) 125, pre-operative albumin concentration (AC), optimal cytoreductive surgery (CRS) and GOLPH3L expression correlate significantly with overall survival (OS). Multivariate analysis revealed that GOLPH3L expression was an independent prognostic factor for OS of patients with EOC (102 months versus 72 months; P=0.013). What's more, knocked down of GOLPH3L with small interfering RNA (siRNA) technology of OVCAR3 and SKOV3 cell lines reduced cell viability obviously, compared to the negative control and blank control groups.

Conclusions: Our data show that increased expression of GOLPH3L is associated with poor prognosis of patients with EOC and may act as a novel, useful and independent prognostic indicator. Therefore, further studies are warranted.

Tuesday, September 13, 2016 8:19 PM|Ying Jin, Li-ping Feng, Xiang Jiang, Yong-xue Wang, Jie Yin, Zi-ping Yang, Yan Li, Ling-ya Pan|Journal of Cancer (RSS 2.0)|Labels: ovarian cancer

Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological malignancies and is rarely cured in the recurrent setting, mainly because of progressive chemoresistance, especially platinum resistance. In our previous studies, the platinum-resistance-related protein, annexin A3, was selected by comparative proteomics. In this study, we detected serum annexin A3 levels using a self-developed chemiluminescence immunoassay kit in a prospective EOC patient cohort. We also evaluated the capacity of serum annexin A3 levels to predict platinum resistance. Serum annexin A3 levels in healthy women exhibited a similar normal distribution (Z=0.723, P=0.673), allowing determination of a normal cutoff level of 0.11-1.45 ng/mL. Of the 89 EOC patients, 21 were platinum resistant and 68 were platinum sensitive. Residual disease after primary surgery (p=0.004) and serum annexin A3 levels (p=0.036) were both independent factors associated with platinum resistance. The AUC was 0.733 (95% confidence interval (CI), 0.627-0.823). The optimal cutoff value for serum annexin A3 levels was 2.05 ng/mL. Multivariate logistic analysis showed that expression of annexin A3 as assessed by immunohistochemistry (P=0.005) and residual tumor size (P=0.000) had a significant influence on platinum resistance. The AUC of ROC curve of annexin A3 expression by immunohistochemistry was 0.664 (95% CI, 0.554-0.763) and the cut off value was “>=moderate scores”. In conclusion, we demonstrate that annexin A3 is a secreted protein that may be measured in the peripheral blood using a self-developed, chemiluminescence immunoassay kit. Serum annexin A3 levels may be a potential predictor of platinum resistance in epithelial ovarian cancer patients.

Tuesday, September 13, 2016 8:19 PM|Ming Chen, Ying Jin, Yalan Bi, Yan Li, Ying Shan, Lingya Pan|Journal of Cancer (RSS 2.0)|Labels: ovarian cancer

Object: To assess the effects of lymphovascular space invasion (LVSI) on cancer recurrence and survival in patients with primary epithelial ovarian cancer.

Methods: A retrospective study was conducted of patients with stage I-IV primary epithelial ovarian cancer who underwent cytoreductive surgery. LVSI is defined as the presence of tumor cells within an endothelium-lined space, and the patients' pathologic slides were reevaluated by gynecological pathologists. Survival analysis was performed to compare risk factors.

Results: A total of 492 patients were included in the analysis. The incidence of LVSI was 58.5% in our cohort (288 cases), and it was significantly associated with advanced stage, high-grade serous histology, high grade, and lymph node metastasis (P<0.001). Kaplan-Meier analysis demonstrated that LVSI was only correlated with decreased PFS (5-year rate, 39% vs. 66%, P<0.001) and OS (5-year rate, 44% vs. 78%, P<0.001) in patients at early stage but not at advanced stage (5-year rate, PFS: 14% vs. 11%, P<0.001; OS: 29% vs. 29%, P=0.141). Multivariate analysis showed that LVSI remained a significant variable with PFS and OS in early-stage ovarian cancer (PFS: HR 2.29, 95% CI 1.45-3.57; OS: HR 2.20, 95% CI 1.59-3.44, both P<0.001).

Conclusion: LVSI is an independent predictor of progression and survival in patients with primary epithelial ovarian cancer at early stage but not at advanced stage.

Tuesday, September 13, 2016 2:05 PM|Hyejin Kim, Ji-Sook Hwang, Bogman Lee, Jinpyo Hong, Soojin Lee|Journal of Cancer|Labels: ovarian cancer

Neuronal growth regulator 1 (NEGR1) has become a great interest based on the recent findings that its genetic alteration is implicated in human obesity and human dyslexia. By analyzing the gene expression profiles of tumor biopsies and normal tissues, we identified NEGR1 as a commonly down-regulated gene in many types of human cancer tissues. NEGR1 contains a C-terminal GPI anchor attachment site and is primarily localized to cell membrane rafts, especially in cell-to-cell contacting areas. The oncogenic phenotype was clearly attenuated when NEGR1 was overexpressed in the human ovarian cancer cell line SKOV-3. Furthermore, cell aggregation and neurite outgrowth was greatly increased by NEGR1 overexpression. On the contrary, cell migration and invasion was increased in NEGR1-depleted cells, suggesting that NEGR1 may contribute to tumor suppression. Taken together, we suggest that NEGR1 is a raft-associated extracellular protein that may participate in cell recognition and interaction, which is important in growth control and malignant transformation.

Tuesday, September 13, 2016 2:05 PM|Federica Tomao, Anselmo Papa, Martina Strudel, Luigi Rossi, Giuseppe Lo Russo, Pierluigi Benedetti Panici, Francesca Romana Ciabatta, Silverio Tomao|Journal of Cancer|Labels: ovarian cancer

Currently we are more and more improving our knowledge about the characteristics and the role of cancer stem cells in human cancer. Particularly we have realized that self-renewing ovarian cancer stem cells (CSCs) or ovarian cancer-initiating cells, and mesenchymal stem cells (SCs) too, are probably implicated in the etiopathogenesis of epithelial ovarian cancer (EOC). There is clear evidence that these cells are also involved in its intra- and extra-peritoneal diffusion and in the occurrence of chemo-resistance. In assessing the molecular characteristics of ovarian CSCs, we have to take note that these cellular populations are rare and the absence of specific cell surface markers represents a challenge to isolate and identify pure SC populations. In our review, we focused our attention on the molecular characteristics of epithelial ovarian CSCs and on the methods to detect them starting from their biological features. The study of ovarian CSCs is taking on an increasingly important strategic role, mostly for the potential therapeutic application in the next future.

Tuesday, September 13, 2016 2:05 PM|Charlotte S Marcus, G Larry Maxwell, Kathleen M Darcy, Chad A Hamilton, William P McGuire|Journal of Cancer|Labels: ovarian cancer

Epithelial ovarian cancer is the leading cause of death among gynecologic malignancies. Treatment of recurrent ovarian cancer remains a challenge despite advances in surgical and chemotherapeutic options. A goal of many providers is to detect recurrences as early as possible and initiate treatment though there is controversy as to whether this impacts outcome. Elevations in CA125 and radiological findings may precede symptoms of recurrence by several months. While detection of recurrences by physical exam alone is unusual, a thorough exam in conjunction with reported symptoms and elevated CA125 is sufficient to detect 80-90% of recurrences. A spiral CT scan may be used to confirm recurrence in the setting of asymptomatic CA125 elevation and a PET/CT can yield additional insight if the CT is inconclusive. Initiating chemotherapy prior to the development of symptoms, even in the setting of elevated CA125, does not impact overall survival primarily because the efficacy of available treatments in the recurrent setting is poor. More information about tumor biology and ways to predict which patients will benefit from available treatment options is required. Consequently, the approach to post-treatment surveillance should be individualized taking into account the clinical benefit of the second-line therapy, versus the costs and morbidity of the surveillance method.

Thursday, September 8, 2016 6:00 PM|admin|Labels: ovarian cancer

The Food and Drug Administration (FDA) has issued a safety communication advising against use of tests being marketed as ovarian cancer screening tests.

The FDA notes that there are currently no screening tests for ovarian cancer that are sensitive enough to reliably screen for ovarian cancer without a high number of inaccurate results. The Agency issued the safety alert due to concerns that inaccurate negative screening results may delay effective preventive treatments for women who show no symptoms, but who are still at increased risk for developing ovarian cancer. In other cases, false-positive results may lead to unnecessary testing and/or surgery.

The FDA’s recommendation is consistent with recommendations from the U.S. Preventive Services Task Force (USPSTF). The USPSTF recommends against screening for ovarian cancer in asymptomatic women, although this recommendation does not extend to women with known genetic mutations that increase their risk for ovarian cancer.

Ovarian cancer is the fifth leading cause of cancer-related death among women in the United States.

 

Food and Drug Administration (FDA). The FDA recommends against using screening tests for ovarian cancer screening: FDA Safety Communication. September 7, 2016. Available at: click here. Accessed September 8, 2016.

Thursday, September 8, 2016 1:00 AM|MIT Biotech Group - Essential Biotech RSS Feed|Labels: BRCA, ovarian cancer, regulatory
Clovis Oncology Inc. (NASDAQ:CLVS) gained $3.66 (15%) to $28.01 on Thursday after it said in a regulatory filing that FDA does not plan to hold an advisory committee meeting to discuss the company's NDA for rucaparib (CO-338).Last month, FDA granted Priority Review to the application seeking accelerated approval of rucaparib as monotherapy in patients with germline or somatic BRCA-mutated advanced ovarian cancer who have received multiple prior chemotherapies. Rucaparib's PDUFA date is Feb. 23, 2017.Clovis has exclusive, worldwide rights to the oral inhibitor of PARP-1 and PARP-2 from Pfizer Inc. (NYSE:PFE). It has breakthrough therapy designation from FDA in the indication.
Wednesday, September 7, 2016 8:45 AM|Terry, K. L., Schock, H., Fortner, R. T., Hüsing, A., Fichorova, R. N., Yamamoto, H. S., Vitonis, A. F., Johnson, T., Overvad, K., Tjonneland, A., Boutron-Ruault, M.-C., Mesrine, S., Severi, G., Dossus, L., Rinaldi, S., Boeing, H., Benetou, V., Lagiou, P., Trichopoulou, A., Krogh, V., Kuhn, E., Panico, S., Bueno-de-Mesquita, H. B., Onland-Moret, N. C., Peeters, P. H., Gram, I. T., Weiderpass, E., Duell, E. J., Sanchez, M.-J., Ardanaz, E., Etxezarreta, N., Navarro, C., Idahl, A., Lundin, E., Jirström, K., Manjer, J., Wareham, N. J., Khaw, K.-T., Byrne, K. S., Travis, R. C., Gunter, M. J., Merritt, M. A., Riboli, E., Cramer, D. W., Kaaks, R.|Clinical Cancer Research Online First Articles|Labels: ovarian cancer

Purpose: About 60% of ovarian cancers are diagnosed at late stage, when 5-year survival is less than 30% in contrast to 90% for local disease. This has prompted search for early detection biomarkers. For initial testing, specimens taken months or years before ovarian cancer diagnosis are the best source of information to evaluate early detection biomarkers. Here we evaluate the most promising ovarian cancer screening biomarkers in prospectively collected samples from the European Prospective Investigation into Cancer and Nutrition study.

Experimental Design: We measured CA125, HE4, CA72.4, and CA15.3 in 810 invasive epithelial ovarian cancer cases and 1,939 controls. We calculated the sensitivity at 95% and 98% specificity as well as area under the receiver operator curve (C-statistic) for each marker individually and in combination. In addition, we evaluated marker performance by stage at diagnosis and time between blood draw and diagnosis.

Results: We observed the best discrimination between cases and controls within 6 months of diagnosis for CA125 (C-statistic = 0.92), then HE4 (0.84), CA72.4 (0.77), and CA15.3 (0.73). Marker performance declined with longer time between blood draw and diagnosis and for earlier staged disease. However, assessment of discriminatory ability at early stage was limited by small numbers. Combinations of markers performed modestly, but significantly better than any single marker.

Conclusions: CA125 remains the single best marker for the early detection of invasive epithelial ovarian cancer, but can be slightly improved by combining with other markers. Identifying novel markers for ovarian cancer will require studies including larger numbers of early-stage cases. Clin Cancer Res; 22(18); 1–12. ©2016 AACR.

See related commentary by Skates, p. 4542

Tuesday, September 6, 2016 10:39 AM|Lo, C. S., Sanii, S., Kroeger, D. R., Milne, K., Talhouk, A., Chiu, D. S., Rahimi, K., Shaw, P. A., Clarke, B. A., Nelson, B. H.|Clinical Cancer Research Online First Articles|Labels: PD-1/PD-L1, ovarian cancer

Purpose: Some forms of chemotherapy can enhance anti-tumor immunity through immunogenic cell death, resulting in increased T cell activation and tumor infiltration. Such effects could potentially sensitize tumors to immunotherapies, including checkpoint blockade. We investigated whether platinum- and taxane-based chemotherapy for ovarian cancer induces immunological changes consistent with this possibility. Methods: Matched pre- and post-neoadjuvant chemotherapy tumor samples from 26 high-grade serous carcinoma (HGSC) patients were analyzed by immunohistochemistry (IHC) for a large panel of immune cells and associated factors. The prognostic significance of post-chemotherapy TIL patterns was assessed in an expanded cohort (n=90). Results: Neoadjuvant chemotherapy was associated with increased densities of CD3+, CD8+, CD8+ TIA-1+, PD-1+ and CD20+ TIL. Other immune subsets and factors were unchanged, including CD79a+ CD138+ plasma cells, CD68+ macrophages, and MHC class I on tumor cells. Immunosuppressive cell types were also unchanged, including FoxP3+ PD-1+ cells (putative regulatory T cells), IDO-1+ cells, and PD-L1+ cells (both macrophages and tumor cells). Hierarchical clustering revealed three response patterns: (1) TILhigh tumors showed increases in multiple immune markers after chemotherapy; (2) TILlow tumors underwent similar increases, achieving patterns indistinguishable from the first group; and (3) TILnegative cases generally remained negative. Despite the dramatic increases seen in the first two patterns, post-chemotherapy TIL showed limited prognostic significance. Conclusion: Chemotherapy augments pre-existing TIL responses but fails to relieve major immune suppressive mechanisms or confer significant prognostic benefit. Our findings provide rationale for multi-pronged approaches to immunotherapy tailored to the baseline features of the tumor microenvironment.

Monday, August 29, 2016 1:31 PM|Liu, J. F., Palakurthi, S., Zeng, Q., Zhou, S., Ivanova, E., Huang, W., Zervantonakis, I. K., Selfors, L. M., Shen, Y., Pritchard, C. C., Zheng, M., Adleff, V., Papp, E., Piao, H., Novak, M., Fotheringham, S., Wulf, G., English, J., Kirschmeier, P. T., Velculescu, V. E., Paweletz, C. P., Mills, G. B., Livingston, D. M., Brugge, J. S., Matulonis, U. A., Drapkin, R.|Clinical Cancer Research Online First Articles|Labels: ovarian cancer

Purpose: Ovarian cancer is the leading cause of death from gynecologic malignancy in the United States, with high rates of recurrence and eventual resistance to cytotoxic chemotherapy. Model systems that allow for accurate and reproducible target discovery and validation are needed to support further drug development in this disease. Experimental Design: Clinically-annotated patient-derived xenograft (PDX) models were generated from tumor cells isolated from the ascites or pleural fluid of patients undergoing clinical procedures. Models were characterized by immunohistochemistry and by molecular analyses. Each PDX was luciferized to allow for reproducible in vivo assessment of intraperitoneal tumor burden by bioluminescent imaging (BLI). Plasma assays for CA125 and human LINE-1 were developed as secondary tests of in vivo disease burden. Results: 14 clinically annotated and molecularly characterized luciferized ovarian PDX models were generated. Luciferized PDX models retain fidelity to both the non-luciferized PDX and the original patient tumor, as demonstrated by immunohistochemistry, array CGH, and targeted and whole-exome sequencing analyses. Models demonstrated diversity in specific genetic alterations and activation of PI3K signaling pathway members. Response of luciferized PDX models to standard of care therapy could be reproducibly monitored by BLI or plasma markers. Conclusions: We describe the establishment of a collection of 14 clinically annotated and molecularly characterized luciferized ovarian PDX models in which orthotopic tumor burden in the intraperitoneal space can be followed by standard and reproducible methods. This collection is well-suited as a platform for proof-of-concept efficacy and biomarker studies and for validation of novel therapeutic strategies in ovarian cancer.

Tuesday, August 16, 2016 1:55 AM|Soochi Kim, Boyun Kim, Yong Sang Song|Cancer Science|Labels: ovarian cancer
Malignant ascites constitute a unique tumor microenvironment providing a physical structure for the accumulation of cellular and acellular components. Ascites is initiated and maintained by physical and biological factors resulting from underlying disease and forms an ecosystem that contributes to disease progression. It has been demonstrated that the cellular contents and the molecular signatures of ascites change continuously during the course of a disease. Over the past decade, increasing attention has been given to the characterization of components of ascites and their role in the progression of ovarian cancer, the most malignant gynecologic cancer in women. This review will discuss the role of ascites in disease progression, in terms of modulating cancer cell behavior and contributing to tumor heterogeneity. The ascites of cancer provide a physical structure for the accumulation of cellular and acellular components. The resulting tumor microenvironment contributes to the disease progression and tumor heterogeneity, as well as poor prognosis in ovarian cancer.
Sunday, August 14, 2016 10:05 PM|Tiper, I. V., Temkin, S. M., Spiegel, S., Goldblum, S. E., Giuntoli, R. L., Oelke, M., Schneck, J. P., Webb, T. J.|Clinical Cancer Research recent issues|Labels: VEGF, ovarian cancer

Purpose: Natural killer T (NKT) cells are important mediators of antitumor immune responses. We have previously shown that ovarian cancers shed the ganglioside GD3, which inhibits NKT-cell activation. Ovarian cancers also secrete high levels of VEGF. In this study, we sought to test the hypothesis that VEGF production by ovarian cancers suppresses NKT-cell–mediated antitumor responses.

Experimental Design: To investigate the effects of VEGF on CD1d-mediated NKT-cell activation, a conditioned media model was established, wherein the supernatants from ovarian cancer cell lines (OV-CAR-3 and SK-OV-3) were used to treat CD1d-expressing antigen-presenting cells (APC) and cocultured with NKT hybridomas. Ovarian cancer–associated VEGF was inhibited by treatment with bevacizumab and genistein; conditioned medium was collected, and CD1d-mediated NKT-cell responses were assayed by ELISA.

Results: Ovarian cancer tissue and ascites contain lymphocytic infiltrates, suggesting that immune cells traffic to tumors, but are then inhibited by immunosuppressive molecules within the tumor microenvironment. OV-CAR-3 and SK-OV-3 cell lines produce high levels of VEGF and GD3. Pretreatment of APCs with ascites or conditioned medium from OV-CAR-3 and SK-OV-3 blocked CD1d-mediated NKT-cell activation. Inhibition of VEGF resulted in a concomitant reduction in GD3 levels and restoration of NKT-cell responses.

Conclusions: We found that VEGF inhibition restores NKT-cell function in an in vitro ovarian cancer model. These studies suggest that the combination of immune modulation with antiangiogenic treatment has therapeutic potential in ovarian cancer. Clin Cancer Res; 22(16); 4249–58. ©2016 AACR.

Sunday, August 14, 2016 10:05 PM|Liang, L., Mercado-Uribe, I., Niu, N., Jiang, Y., Cheng, W., Broaddus, R., Bast, R., Mills, G., Sood, A. K., Liu, J.|Clinical Cancer Research recent issues|Labels: PARP, ovarian cancer

Ovarian cancer is the most lethal gynecological malignancy. The majority of ovarian cancer patients are diagnosed at an advanced stage of disease, and the lack of good early screening and diagnostic tests is one of the reasons for the low overall survival rate. Moreover, there is no good marker to predict patients' response to chemotherapy. Patient-derived xenografts (PDXs) have become the most promising preclinical model for gynecologic malignances. We have successfully established 22 PDX models derived from ovarian cancer patients' surgical specimens implanted into severe combined immunodeficient (SCID) mice, non-obese diabetic (NOD)-SCID or Nude mice. The majority of the PDX models were generated from patients' samples diagnosed with high-grade serous carcinoma including 3 with BRCA1/2 mutations, as well as less common types of ovarian cancers such as low-grade serous, endometrioid, mucinous carcinomas, and carcinosarcoma. PDXs have been established from solid masses as well as from ascites. We have optimized protocol for establishing ovarian PDXs including implantation and collection methods, tumor type (solid versus ascites), and type of mouse strains used. Using SCID mice, our success rate exceeded 80% and recent data indicated that the success rate in NOD/SCID mice was higher. The link between the pathology and PDX core, the "triage protocol" and ongoing PARP inhibitor trials will provide an important array of PDXs including pre- and post-treatment PDXs for exploration for biomarkers as well as for co-clinical trials to validate the utility of rational drug combinations. All models were validated using short tandem repeats (STR) and compared to the H&E and immunohistochemistry stains from the matching patient's tissue. We also examined the expression of B7-H4, a novel member of the B7 family immune checkpoint regulators, in 9 patient-derived xenografts (PDXs) of high-grade ovarian serous carcinoma. Our data showed that B7-H4 proteins were expressed in 8 of 9 PDX models of high-grade serous carcinoma, suggesting that PDXs may be useful for studying immunotherapy.

Citation Format: Li Liang, Imelda Mercado-Uribe, Na Niu, Yi Jiang, Wenjun Cheng, Russell Broaddus, Robert Bast, Gordon Mills, Anil K. Sood, Jinsong Liu. Establishment of Patient-Derived Xenograft (PDX) Models of Ovarian Cancer. [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 B22.

Sunday, August 14, 2016 10:05 PM|Weroha, S. J.|Clinical Cancer Research recent issues|Labels: PARP, ovarian cancer

Ovarian cancer is the most lethal gynecologic cancer and the fifth most common cause of cancer death among women in the United States. Although there have been incremental improvements in progression free survival over the last several decades from advances in surgical technique and combination-chemotherapy strategies, overall survival has essentially remained unchanged. Although novel therapeutics have the potential to impact overall survival and lead to more cures, drug development in this area has been limited by the availability of clinically relevant models that recapitulate the molecular and phenotypic characteristics of primary ovarian cancers.

To overcome this barrier, we have developed primary patient derived xenograft (PDX) models from every consenting patient having primary debulking surgery at Mayo Clinic since 2010 (>550 unique patients). Fresh tissues are minced and injected intraperitoneally into severe combined immunodeficient (SCID) mice without enzymatic digestion or surgical implantation. The patient-to-mouse time is typically <1.5 hours and the engraftment rate is 73%.

Ovarian PDX models have demonstrated their utility as patient surrogates. The histologic diversity is representative of the population from which they are derived with high-grade serous comprising most of the models. However, the ovarian PDX bank also includes less-common subtypes, such as clear cell, mucinous, and carcinosarcoma. Histologic and genomic fidelity is maintained within early-passage tumors. Moreover, the patient's clinical response to carboplatin and paclitaxel (a standard front-line therapy for ovarian cancer) demonstrates high correlation to the matched PDX tumor response in vivo, supporting their relevance as patient surrogates.

The models have been used for preclinical drug development and biomarker validation. One example is the correlation between PARPi response in PDXs and their homologous recombination deficiency (HRD) score. All models with a low HRD score, <42, failed to respond to PARP inhibition while models with a high HRD score showed enrichment for response to a PARPi.

Ovarian PDXs are also being used to direct patient care in a clinical trial setting at all three Mayo Clinic sites (MN, FL, and AZ). Tumors are collected at the time of debulking surgery for heterotransplantation. Subsequent xenografts are treated with standard first-line chemotherapy, similar to their matched patient in the clinic, and then PDXs are treated with standard ovarian cancer second-line therapies: liposomal doxorubicin, topotecan, gemcitabine, and paclitaxel. When patients develop platinum-resistant recurrent cancer, the chemotherapy response in the PDX is used to direct therapy in the clinic.

Many challenges continue for ovarian cancer PDX models. The use of immunocompromised mice limits the ability to study the involvement of immunity in chemotherapy responsiveness. In addition, these models are not ideal for testing novel immunotherapies, such as the immune check point inhibitors. Further work to overcome these and other limitations are needed.

Citation Format: S. John Weroha. Ovatars in preclinical drug development and clinical trial for ovarian cancer patients. [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 IA11.

Sunday, August 14, 2016 10:05 PM|Dobbin, Z., Cornelison, R., Katre, A. K., Schneider, D. A., Watters, K., Coscia, F., Lengyel, E., Buechlein, A., Fang, F., Nephew, K., Landen, C. N.|Clinical Cancer Research recent issues|Labels: ovarian cancer

Objectives: The objectives of this study were to use the heterogeneity of the patient-derived xenograft (PDX) model to characterize the surviving population for de novo mediators of chemotherapy resistance, and subsequently target pathways contributing to that resistance.

Methods: Tumors removed during primary tumor-reductive surgery were implanted directly into SCID mice, either subcutaneously and intraperitoneally. Mice with PDX tumors were treated with combination carboplatin/paclitaxel for 4 weeks. In addition, chemoresistant models were developed by treatment until complete response was achieved, and recurrent tumors retreated until resistant. Patient tumors, developing PDX tumors, and post-chemo surviving residual tumors were subjected to qPCR arrays, RNA-Seq, Methyl-Seq, and proteomic analysis; and IHC for Ki-67 and cancer stem cell markers CD133, ALDH1, and CD44. The Pol-I inhibitor CX-5461 was used to treat five PDX models.

Results: At the mRNA level, the original patient tumors were similar to PDX tumors in mice as assessed by an 84-oncogene expression panel. Subcutaneous and intraperitoneal tumors were also remarkably similar. Patient responses correlated well with responses in mice. Proteomic analysis identified 14,023 unique proteins, of which approximately 30% were murine, and 70% were human in each sample. A total of 1,202 of human proteins were found to be differently expressed (p-value < 0.01) between patient and PDX tumors. Of these, 996 (82.9%) were reduced in the PDX model, and predominantly participants in the immune system. PDX tumors collected after chemotherapy showed that the surviving population was significantly more dormant than the original tumor (Ki-67 67% versus 31%, P<0.01), and enriched in all three cancer stem cell populations (2.1-4.7 fold, p<0.05). Principle component analysis of both RNA-Seq and proteomic data show that sensitive and resistant tumors were much more similar to one another than to tumors from different patients, suggesting a limited number of genes contributing to chemoresistance. IPA analysis of RNA-Seq data from treated and untreated PDX tumor pairs demonstrated that the most commonly enriched pathways are those of Protein Kinase A, GNRH, Sphingosine-1-phosphate, and alpha-adrenergic signaling. Additionally, numerous regulators of ribosomal synthesis were significantly altered by treatment. In vivo, 5 PDX models were treated with CX-5461; two had progression, one had stable disease, one had a 60% reduction in tumor growth, and one had a complete response to single agent therapy, still without recurrence after 3 months.

Conclusion: The ovarian-PDX model exhibits consistent molecular and biologic similarity to patient tumors. Post-chemo tumors reveal multiple pathways to be consistently altered. Taking this information back to the PDX model demonstrated that inhibition of ribosomal RNA synthesis was highly effective, offering a novel opportunity to preferentially target the chemoresistant population in ovarian cancer.

Citation Format: Zachary Dobbin, Robert Cornelison, Ashwini K. Katre, David A. Schneider, Karen Watters, Fabian Coscia, Ernst Lengyel, Aaron Buechlein, Fang Fang, Kenneth Nephew, Charles N. Landen, Jr.. Identification and targeting mediators of chemoresistance using the patient-derived xenograft model of ovarian cancer. [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 B39.

Friday, August 12, 2016 12:58 PM|Bandera, E. V., Lee, V. S., Rodriguez-Rodriguez, L., Powell, B., Kushi, L. H.|Clinical Cancer Research Online First Articles|Labels: ovarian cancer

Purpose: Among ovarian cancer patients, African American (AA) women experience poorer survival compared to other race/ethnicity groups. This has been attributed to differences in access to health care. Experimental Design: We evaluated racial/ethnic differences in chemotherapy dosing and survival in a cohort study among members of Kaiser Permanente Northern California, and thus with equivalent access to health care. Analyses included epithelial invasive ovarian cancer cases (n=793) receiving adjuvant first-line therapy of carboplatin and paclitaxel with curative intent, with median follow-up of 50 months. Relative dose intensity (RDI) was computed for carboplatin and paclitaxel separately as dose administered/week divided by expected dose/week, and average RDI (ARDI) was then calculated for the regimen. Proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) after adjusting for relevant covariates. Results: Compared to whites, AAs were more likely to have dose reduction (ARDI<85%), treatment delay, and early discontinuation. Hispanics were also more likely to have dose reduction, but less likely to have early discontinuation or treatment delay. After controlling for prognostic factors including ARDI, AA women had the worst survival. Compared to whites, adjusted HRs (95% CI) for overall mortality were 1.56 (1.01-2.39) for AA; 0.89 (0.61-1.31) for Asians; and 1.41 (0.98-2.04) for Hispanics. Findings for ovarian cancer-specific mortality were similar. Conclusions: Disparities in ovarian cancer treatment and survival in AA persisted among women with equal access to care. These findings warrant further evaluation of biological, personal, and social factors that may be responsible for these differences.

Thursday, August 11, 2016 6:00 PM|Claus Storgaard Sørensen|Nature Reviews Cancer - Issue - nature.com science feeds|Labels: BRCA, ovarian cancer

Nature Reviews Cancer 16, 599 (2016). doi:10.1038/nrc.2016.72

Authors: Finn Cilius Nielsen, Thomas van Overeem Hansen & Claus Storgaard Sørensen

Genetic abnormalities in the DNA repair genes BRCA1 and BRCA2 predispose to hereditary breast and ovarian cancer (HBOC). However, only approximately 25% of cases of HBOC can be ascribed to BRCA1 and BRCA2 mutations. Recently, exome sequencing has uncovered substantial locus

Wednesday, August 10, 2016 10:00 PM|EurekAlert! - Cancer Research News|Labels: ovarian cancer, clinical trial
(Pharmamar) PharmaMar announces that it has received the approval from the Independent Data Monitoring Committee (IDMC) to continue with the pivotal CORAIL study of PM1183 (lurbinectedin) in patients with platinum-resistant ovarian cancer up to the recruitment of the 420 patients established in the protocol.
Tuesday, August 9, 2016 10:29 AM|Sundar, S., Rick, C., Dowling, F., Au, P., Snell, K., Rai, N., Champaneria, R., Stobart, H., Neal, R., Davenport, C., Mallett, S., Sutton, A., Kehoe, S., Timmerman, D., Bourne, T., Van Calster, B., Gentry-Maharaj, A., Menon, U., Deeks, J., on behalf of the ROCkeTS study group, Nagar, Abedin, Jermy, Ghazal, Duncan, Hughes, Willett, Abdi, Keating, Kaushik, Roberts, Sengupta, Sharma, Balogun, Khan, Rai, Ames, Johnson, Nagaraju, Butcher, Vitta, McGrady, Kent, Sinha|BMJ Open Protocol|Labels: ovarian cancer
Introduction

Ovarian cancer (OC) is associated with non-specific symptoms such as bloating, making accurate diagnosis challenging: only 1 in 3 women with OC presents through primary care referral. National Institute for Health and Care Excellence guidelines recommends sequential testing with CA125 and routine ultrasound in primary care. However, these diagnostic tests have limited sensitivity or specificity. Improving accurate triage in women with vague symptoms is likely to improve mortality by streamlining referral and care pathways. The Refining Ovarian Cancer Test Accuracy Scores (ROCkeTS; HTA 13/13/01) project will derive and validate new tests/risk prediction models that estimate the probability of having OC in women with symptoms. This protocol refers to the prospective study only (phase III).

Methods and analysis

ROCkeTS comprises four parallel phases. The full ROCkeTS protocol can be found at http://www.birmingham.ac.uk/ROCKETS. Phase III is a prospective test accuracy study. The study will recruit 2450 patients from 15 UK sites. Recruited patients complete symptom and anxiety questionnaires, donate a serum sample and undergo ultrasound scored as per International Ovarian Tumour Analysis (IOTA) criteria. Recruitment is at rapid access clinics, emergency departments and elective clinics. Models to be evaluated include those based on ultrasound derived by the IOTA group and novel models derived from analysis of existing data sets. Estimates of sensitivity, specificity, c-statistic (area under receiver operating curve), positive predictive value and negative predictive value of diagnostic tests are evaluated and a calibration plot for models will be presented. ROCkeTS has received ethical approval from the NHS West Midlands REC (14/WM/1241) and is registered on the controlled trials website (ISRCTN17160843) and the National Institute of Health Research Cancer and Reproductive Health portfolios.

Wednesday, July 27, 2016 11:11 AM|LOZNEANU, L., PINCIROLI, P., CIOBANU, D. A., CARCANGIU, M. L., CANEVARI, S., TOMASSETTI, A., CĂRUNTU, I.-D.|Anticancer Research recent issues|Labels: ovarian cancer

Background/Aim: The activation of the membrane tyrosine kinase AXL is implicated in the migration and invasion in several carcinomas, including ovarian cancer. Herein, we investigated the association of the expression of AXL transcript and protein to the aggressiveness of ovarian cancer, as well as to patient outcome. Materials and Methods: Overall and relapse-free survival were determined with respect to AXL transcript levels by computational analysis on two publicly available datasets containing data of gene expression from high-grade ovarian cancers (n=776). Immunohistochemical evaluation of AXL protein expression was then performed using a proprietary tissue microarray consisting of 62 ovarian cancers of different histology, grading and staging. Expression was analyzed for association with clinicopathological parameters, including survival. Results: In both analyzed datasets, AXL transcript expression was significantly associated to both overall and relapse-free survival in high-grade ovarian cancers. Membrane expression of AXL protein was observed in 89% of the analyzed ovarian cancers. A significant correlation was found between AXL expression and serous histologic subtype, higher tumor grade and type II tumors. No significant association between AXL protein expression and patient survival was found in our cohort. AXL is frequently expressed in high-grade serous ovarian cancers and its expression is significantly associated to tumors displaying poor prognosis. Conclusion: AXL is a potential prognostic marker for the most aggressive ovarian carcinomas.

Tuesday, July 26, 2016 6:00 PM|Elke Pogge von Strandmann, Rolf Müller|Trends in Molecular Medicine|Labels: ovarian cancer
Ovarian cancer is a deadly disease, largely because of relapse and chemotherapy resistance. Common genetic mechanisms causing drug resistance have not been identified. A recent study unravels a novel and unexpected pathway involving the transfer of microvesicle-encapsulated miRNA from omental adipocytes and fibroblasts, to cancer cells.
Tuesday, July 19, 2016 9:22 AM|Perales-Puchalt, A., Svoronos, N., Rutkowski, M. R., Allegrezza, M. J., Tesone, A. J., Payne, K. K., Wickramasinghe, J., Nguyen, J. M., O'Brien, S. W., Gumireddy, K., Huang, Q., Cadungog, M., Connolly, D. C., Tchou, J., Curiel, T. J., Conejo-Garcia, J. R.|Clinical Cancer Research Online First Articles|Labels: ovarian cancer

Purpose: Define the safety and effectiveness of T-cells re-directed against Follicle-Stimulating Hormone Receptor (FSHR)-expressing ovarian cancer cells. Experimental Design: FSHR expression was determined by Western-blot, immunohistochemistry and Q-PCR in 77 human ovarian cancer specimens from 6 different histological subtypes and 20 human healthy tissues. The effectiveness of human T-cells targeted with full-length FSH in vivo was determined against a panel of patient-derived xenografts. Safety and effectiveness were confirmed in immunocompetent tumor-bearing mice, using constructs targeting murine FSHR and syngeneic T-cells. Results: FSHR is expressed in gynecologic malignancies of different histological types, but not in non-ovarian healthy tissues. Accordingly, T-cells expressing full-length FSHR-re-directed chimeric receptors mediate significant therapeutic effects (including tumor rejection) against a panel of patient-derived tumors in vivo. In immunocompetent mice growing syngeneic, orthotopic, and aggressive ovarian tumors, fully murine FSHR-targeted T-cells also increased survival without any measurable toxicity. Notably, chimeric receptors enhanced the ability of endogenous tumor-reactive T-cells to abrogate malignant progression upon adoptive transfer into naïve recipients subsequently challenged with the same tumor. Interestingly, FSHR-targeted T-cells persisted as memory lymphocytes without noticeable PD-1-dependent exhaustion during end-stage disease, in the absence of tumor cell immunoediting. However, exosomes in advanced tumor ascites diverted the effector activity of this and other chimeric receptor-transduced T-cells away from targeted tumor cells. Conclusions: T-cells redirected against FSHR+ tumor cells with full-length FSH represent a promising therapeutic alternative against a broad range of ovarian malignancies, with negligible toxicity even in the presence of cognate targets in tumor-free ovaries.

Monday, July 11, 2016 1:55 PM|Horikawa, N., Abiko, K., Matsumura, N., Hamanishi, J., Baba, T., Yamaguchi, K., Yoshioka, Y., Koshiyama, M., Konishi, I.|Clinical Cancer Research Online First Articles|Labels: VEGF, ovarian cancer

Purpose:High vascular endothelial growth factor (VEGF) expression in ovarian cancer is an unfavorable prognostic factor. However, the role of VEGF in tumor immunity remains unclear. Here, we examined the impact of VEGF on local immunity, including induction of myeloid-derived suppressor cells (MDSCs), in ovarian cancer. Experimental Design:High-grade serous ovarian cancer (HGSOC) cases were analyzed by gene expression microarray and immunohistochemistry for VEGF, CD8, and CD33. VEGF receptor (VEGFR) 1 and VEGFR2 expression levels on MDSCs were analyzed in a mouse model, and the direct effects of VEGF-A on MDSC expansion were investigated. Gr1+ MDSCs and lymphocyte frequencies were analyzed in control tumors and tumors derived from cells harboring short hairpin RNA targeting Vegf-a. Additionally, the therapeutic effects of anti-Gr-1 antibodies were examined. Results:Microarray analysis revealed the upregulation of several myeloid cell chemoattractants and the downregulation of lymphocytes-related pathways in cases with high VEGF expression. In immunohistochemical analysis, VEGF expression in peritoneal dissemination correlated with MDSC infiltration. Cases with high MDSC infiltration, which was inversely correlated with intratumoral CD8+ T-cell infiltration, exhibited shorter overall survival. In a mouse model, intratumoral MDSCs expressed both VEGFR1 and VEGFR2. MDSC migration and differentiation were augmented by VEGF signaling. Vegf-a knockdown in tumor cells resulted in decreased MDSC infiltration and increased CD8+ T-cell infiltration. Moreover, treatment with anti-Gr-1 antibodies delayed the growth of control tumors, whereas Vegf-a-knockdown tumors were unaffected by anti-Gr-1 antibody treatment. Conclusions:VEGF expression in ovarian cancer induced MDSCs, inhibited local immunity, and contributed to poor prognosis.

Wednesday, July 6, 2016 8:00 AM|Merck News Releases|Attachments|Labels: PD-1/PD-L1, ovarian cancer, clinical trial
Darmstadt, Germany, and New York, US, July 6, 2016 – Merck and Pfizer (NYSE: PFE) today announced the initiation of a Phase III study, JAVELIN Ovarian 100, to evaluate the efficacy and safety of avelumab* in combination with, and/or as follow-on (maintenance) treatment to, platinum-based chemotherapy in patients with locally advanced or metastatic disease (Stage III or Stage IV) with previously untreated epithelial ovarian cancer. JAVELIN Ovarian 100 is the first Phase III study evaluating the addition of an immune checkpoint inhibitor to standard-of-care in first-line treatment for this aggressive disease.
Wednesday, July 6, 2016 6:00 AM|Unknown Author|Press Release|Labels: PD-1/PD-L1, ovarian cancer, clinical trial
Dateline City:
DARMSTADT, Germany & NEW YORK
  • First Phase III trial evaluating the addition of an immune checkpoint inhibitor to standard of care in first-line ovarian cancer
  • New investigational regimen will evaluate avelumab in extending progression-free survival in treatment-naïve women

DARMSTADT, Germany & NEW YORK--(BUSINESS WIRE)--Merck KGaA, Darmstadt, Germany, and Pfizer (NYSE: PFE) today announced the initiation of a Phase III study, JAVELIN Ovarian 100, to evaluate the efficacy and safety of avelumab* in combination with, and/or as follow-on (maintenance) treatment to, platinum-based chemotherapy in patients with locally advanced or metastatic disease (Stage III or Stage IV) with previously untreated epithelial ovarian cancer.

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Sally Beatty, +1-212-733-6566
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Investor Relations:
Ryan Crowe, +1-212-733-8160

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Thursday, June 30, 2016 11:00 PM|O’Donnell, Rachel L.; Kaufmann, Angelika; Woodhouse, Laura; McCormick, Aiste; Cross, Paul A.; Edmondson, Richard J.; Curtin, Nicola J.|International Journal of Gynecological Cancer - Current Issue|Labels: ovarian cancer
imageIntroduction: Epithelial ovarian cancer is recognized to be heterogeneous but is currently treated with a single treatment strategy. Successful patient stratification of emerging chemotherapy agents is dependent upon the availability of reliable biomarkers indicative of the entire tumor. Aim: The aim of this study was to evaluate intertumor and intratumor heterogeneity within a series of epithelial ovarian cancer using homologous recombination (HR) DNA repair status. Methods: Primary cultures generated from ascites and solid tumor from multiple intra-abdominal sites were characterized by their morphology and expression of protein markers. Results were compared with Formalin fixed paraffin embedded tissue pathology. Homologous recombination function was determined by quantification of nuclear Rad51 foci. Growth inhibition (sulforhodamine B) assays were used to calculate the GI50 for cisplatin and rucaparib. Results: Ascites with matched solid tumor were cultured from 25 patients. Concordance in functional HR status between ascites and solid tumor subcultures was seen in only 13 (52%) of 25 patients. Heterogeneity in HR status was seen even in patients with homogeneous histological subtype. Homologous recombination defective cultures were significantly more sensitive to cisplatin and rucaparib. Additionally, intertumor and intratumor heterogeneity was seen between the expression of epithelial and ovarian markers (EpCAM, cytokeratin, CA125, MOC-31, and vimentin). There was no relationship between heterogeneity of HR functional status and antigen expression. Conclusions: Intertumor and intratumor functional HR heterogeneity exists that cannot be detected using histological classification. This has implications for biomarker-directed treatment.
Thursday, June 30, 2016 11:00 PM|Seagle, Brandon-Luke L.; Dandapani, Monica; Yeh, Judy Y.; Shahabi, Shohreh|International Journal of Gynecological Cancer - Current Issue|Labels: WNT, ovarian cancer
imageObjective: Ovarian cancer is the gynecologic malignancy with the highest case-fatality rate due to the development of chemotherapy resistance. Predictors of chemotherapy response are needed to guide chemotherapy selection and improve survival for patients with ovarian cancer. Wnt signaling may impact chemoresistance in ovarian cancer. Methods: We studied The Cancer Genome Atlas patients with ovarian cancer treated with intraperitoneal or intravenous-only adjuvant chemotherapy. Cox regression tested associations of expression of 26 Wnt pathway genes with progression-free survival and overall survival. Permutation tests compared survival between chemotherapy groups stratified by expression. P values are two-tailed. Results: Increased FZD3 was associated with increased survival (intraperitoneal group, overall survival: hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.11–0.72, P = 0.009; progression-free survival: HR, 0.58; 95% CI, 0.37–0.92, P = 0.020) (intravenous-only group, overall survival: HR, 0.85; 95% CI, 0.72–0.99, P = 0.039; progression-free survival: HR, 0.83; 95% CI, 0.73–0.95, P = 0.006). Low FZD3 predicted decreased overall survival after intraperitoneal versus intravenous-only chemotherapy (21.7 vs 33.3 months, P < 0.0001). Increased APC2 was associated with decreased overall survival (HR, 1.22; 95% CI, 1.05–1.42; P = 0.009) and progression-free survival (HR, 1.28; 95% CI, 1.12–1.45; P = 0.0002). Conclusions: Up-regulated tumor Wnt signaling predicts increased ovarian cancer survival. FZD3 may predict benefit from intraperitoneal chemotherapy.
Thursday, June 30, 2016 11:00 PM|Rose, Peter G.; Mahdi, Haider; Jernigan, Amelia; Yang, Bin|International Journal of Gynecological Cancer - Current Issue|Labels: VEGF, ovarian cancer
imageObjectives: The aim of this study was to evaluate the antitumor activity of bevacizumab in low-grade serous ovarian carcinoma (LGSOC). Methods: We retrospectively identified patients with LGSOC treated with bevacizumab. Results: Twelve patients with LGSOC who received bevacizumab were identified. Eleven patients received bevacizumab alone. Only 1 (8.3%) of 12 patients had evidence of a partial response. Ten (90.9%) of the 11 patients were progression free at 6 months. All but 1 patient who received only 2 courses before treatment interruption had a progression-free survival (PFS) of greater than 6 months. The median PFS was 48 months (range, 5–123+ months). Three of the patients reported in this series had extended disease stabilization that lasted for 123+, 48, and 15+ months after progression-free intervals on prior chemotherapy regimens of 2.5, 4, and 7 months, respectively. The median overall survival was not reached at a median follow-up of 32 months, with only 1 of the 12 patients dying of disease. Conclusions: In our series, in patients with LGSOC treated primarily with bevacizumab, primarily as a single agent, a low response rate but very long PFS is observed. In addition, patients have had secondary PFS durations that exceeded their prior PFS, which is a sign of anticancer activity.
Thursday, June 30, 2016 11:00 PM|Stålberg, Karin; Crona, Joakim; Razmara, Masoud; Taslica, Diana; Skogseid, Britt; Stålberg, Peter|International Journal of Gynecological Cancer - Current Issue|Labels: ovarian cancer
imageObjective: This study aimed to perform an integrative genetic analysis of patients with matched serous ovarian cancer having long-term or short-term survival using formalin fixed paraffin-embedded (FFPE) tissue samples. Methods: All patients with serous ovarian carcinoma who underwent surgery between 1998 and 2007 at the Department of Gynaecology, Uppsala University Hospital, Sweden were considered. From this cohort, we selected biomaterial from 2 groups of patients with long-term and short-term survival matched for age, stage, histologic grade, and outcome of surgery. Genomic DNA from FFPE sample was analyzed with SNP array and targeted next-generation sequencing of 26 genes. Results: Forty-three samples (primary tumors and metastases) from 23 patients were selected for genomic profiling, the survival in the subgroups were 134 and 36 months, respectively. We observed a tendency toward increased genomic instability in those with long-term survival with higher proportion of somatic copy number alterations (P = 0.083) and higher average ploidy (P = 0.037). TP53 mutations were found in 50% of the patients. Frequency of TP53 mutations did not differ between the survival groups (P = 0.629). Conclusions: We validated both previous genomic findings in ovarian cancer and the proposed association between increased genomic instability and better survival. These results exemplify that analysis of genomic biomarkers is feasible on archived FFPE tissue.
Thursday, June 30, 2016 11:00 PM|Simmons, Archana R.; Clarke, Charlotte H.; Badgwell, Donna B.; Lu, Zhen; Sokoll, Lori J.; Lu, Karen H.; Zhang, Zhen; Bast, Robert C. Jr; Skates, Steven J.|International Journal of Gynecological Cancer - Current Issue|Labels: ovarian cancer, biomarker diagnostic
imageObjectives: Longitudinal multimarker combinations have the potential to improve sensitivity while maintaining the high specificity required for the early detection of ovarian cancer. The use of multiple markers to improve sensitivity over cancer antigen 125 (CA125) in longitudinal algorithms for early ovarian cancer detection requires the selection of markers with optimal discriminatory power and low longitudinal variance relative to disease-initiated changes. Our objective was to identify a multimarker panel suitable for ovarian cancer, where each individual marker has its own baseline, permitting longitudinal algorithm development. Materials and Methods: In this retrospective study, we measured CA125, human epididymis protein 4 (HE4), matrix metalloproteinase-7 (MMP-7), CA72-4, CA19-9, CA15-3, carcinoembryonic antigen, and soluble vascular cell adhesion molecule (sVCAM) concentrations using immunoassays in pretreatment sera from 142 stage I ovarian cancer cases and 5 annual samples each from 217 healthy controls. After random division into training and validation sets, all possible biomarker combinations were explored exhaustively using linear classifiers to identify the panel with the greatest sensitivity for stage I disease at a high specificity of 98%. To evaluate longitudinal performance of the individual markers, the within-person over time and the between-person coefficient of variation (CV) were estimated. Hierarchical modeling across women of log-concentrations enabled the borrowing of information across subjects to moderate variance estimates given the small number of observations per subject. Results: The 4-marker panel comprising CA125, HE4, MMP-7, and CA72-4 performed with the highest sensitivity (83.2%) at 98% specificity. The within-person CVs were lower for CA125, HE4, MMP-7, and CA72-4 (15%, 25%, 25%, and 21%, respectively) compared with their corresponding between-person CV (49%, 20%, 35%, and 84%, respectively) indicating baselines in healthy volunteers. After simple log-transformations, the within-volunteer variation across volunteers was modeled with a normal distribution permitting parsimonious hierarchical modeling. Conclusions: The multiplex panel chosen is suitable for the early detection of ovarian cancer and the individual markers have their own baseline permitting longitudinal algorithm development.
Wednesday, June 29, 2016 6:00 PM|Robert L Hollis, Charlie Gourley|Cancer Biology & Medicine|Labels: ovarian cancer
Epithelial ovarian cancer represents the most lethal gynecological malignancy in the developed world, and can be divided into fivemain histological subtypes: high grade serous, endometrioid, clear cell, mucinous and low grade serous. These subtypes representdistinct disease entities, both clinically and at the molecular level. Molecular analysis has revealed significant genetic heterogeneityin ovarian cancer, particularly within the high grade serous subtype. As such, this subtype has been the focus of much researcheffort to date, revealing molecular subgroups at both the genomic and transcriptomic level that have clinical implications.However, stratification of ovarian cancer patients based on the underlying biology of their disease remains in its infancy. Here, wesummarize the molecular changes that characterize the five main ovarian cancer subtypes, highlight potential opportunities fortargeted therapeutic intervention and outline priorities for future research.
Monday, June 27, 2016 12:02 PM|Montfort, A., Pearce, O. M. T., Maniati, E., Vincent, B., Bixby, L. M., Böhm, S., Dowe, T., Wilkes, E. H., Chakravarty, P., Thompson, R., Topping, J., Cutillas, P. R., Lockley, M., Serody, J. S., Capasso, M., Balkwill, F. R.|Clinical Cancer Research Online First Articles|Labels: ovarian cancer

Purpose: In high-grade serous ovarian cancer (HGSOC), higher densities of both B cells and the CD8+ T cell infiltrate were associated with a better prognosis. However, the precise role of B cells in the anti-tumor response remains unknown. As peritoneal metastases are often responsible for relapse, our aim was to characterize the role of B cells in the anti-tumor immune response in HGSOC metastases. Experimental Design: Unmatched pre and post-chemotherapy HGSOC metastases were studied. B-cell localization was assessed by immunostaining. Their cytokines and chemokines were measured by multiplex assay and their phenotype was assessed by flow cytometry. Further in vitro and in vivo assays highlighted the role of B cells and plasma cell IgGs in the development of cytotoxic responses and dendritic cell activation. Results: B cells mainly infiltrated lymphoid structures in the stroma of HGSOC metastases. There was a strong B-cell memory response directed at a restricted repertoire of antigens and production of tumor-specific IgGs by plasma cells. These responses were enhanced by chemotherapy. Interestingly, transcript levels of CD20 correlated with markers of immune cytolytic responses and immune complexes with tumor-derived IgGs stimulated the expression of the co-stimulatory molecule CD86 on antigen presenting cells. A positive role for B cells in the anti-tumor response was also supported by B cell depletion in a syngeneic mouse model of peritoneal metastasis. Conclusions: Our data showed that B cells infiltrating HGSOC omental metastases support the development of an anti-tumor response.

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

Background: MicroRNAs are able to control vital tumor biological processes, such as proliferation, tissue transformation and cell migration, as well as apoptosis. One of the micro RNAs, namely miR-1, has been classified as a tumor suppressor, however, preliminary data did not confirm this finding in ovarian cancer (OC) cells. This study examined the impact of miR-1 on OC cell growth. Materials and Methods: Recombinant miR-1 was overexpressed in human OC cell lines OVCAR-3, SK-OV-3, TOV-112D, and TOV-21G. Subsequently, cell growth was analyzed. Results: After transfection, 11- to 487-fold overexpression of miR-1 was detectable in the OC cells. However, no significant differences in proliferation compared to control cells were detected, neither in transiently nor in stably transfected cells. Conclusion: In numerous cancer entities miR-1 is defined as an antiproliferative tumor suppressor. Notably, the present study demonstrated a loss of growth-inhibitory functionality of miR-1 by so far unknown mechanisms, suggesting dysregulated miR-1 signaling or effector cascades in OC cells.

Wednesday, June 22, 2016 9:24 AM|Ikeda, Y., Park, J.-H., Miyamoto, T., Takamatsu, N., Kato, T., Iwasa, A., Okabe, S., Imai, Y., Fujiwara, K., Nakamura, Y., Hasegawa, K.|Clinical Cancer Research Online First Articles|Labels: ovarian cancer

Background; We aimed to clarify the clinical significance of TOPK (T-lymphokine-activated killer cell-originated protein kinase) expression in ovarian cancer and evaluate the possible effect of TOPK inhibitors, OTS514 and OTS964, on ovarian cancer cells. Methods; TOPK expression was examined by immunohistochemistry using 163 samples with epithelial ovarian cancer (EOC). TOPK protein level and FOXM1 transcriptional level in ovarian cancer cell lines were examined by western blot and RT-PCR, respectively. Half-maximum inhibitory concentration (IC50) values against TOPK inhibitors were examined by MTT assay. Using peritoneal dissemination model of ES-2 ovarian cancer cells, we examined in vivo efficacy of OTS514. In addition, cytotoxic effect of OTS514 and OTS964 on 31 patient-derived primary ovarian cancer cells was examined. Results; TOPK was expressed very highly in 84 (52%) of 163 EOC tissues and high TOPK expression was significantly associated with poor progression free survival and overall survival in early-stage cases of EOC (P=0.008 and P=0.006, respectively). Both OTS514 and OTS964 showed significant growth-inhibitory effect on ovarian cancer cell lines with IC50 values of 3.0 - 46 nM and 14 - 110 nM, respectively. TOPK protein and transcriptional level of FOXM1 were reduced by TOPK inhibitors treatment. Oral administration of OTS514 significantly elongated overall survival in ES-2 abdominal dissemination xenograft model, compared with vehicle control (P<0.001). Two drugs showed strong growth-inhibitory effect on primary ovarian cancer cells regardless to tumor sites or histological subtypes. Conclusion; Our results demonstrated the clinical significance of high TOPK expression, and potential of TOPK inhibitors to treat ovarian cancer.

Sunday, June 19, 2016 1:00 AM|Anette Kargo, Parvin Adimi, Karina Dahl Steffensen|International Journal of Cancer Therapy and Oncology|Labels: VEGF, ovarian cancer

Treatment of multiresistant ovarian cancer is palliative and patients have needs for less toxic treatment. Anti-angiogenic treatments have a less toxic profile, and bevacizumab has shown improvement of progression free survival (PFS) in front-line trials. Bevacizumab is generally introduced in combination with chemotherapy; however this case report will describe the use of single-agent bevacizumab for more than five years (102 cycles) in a patient with relapse of advanced ovarian cancer.

Monday, June 6, 2016 4:58 AM|ARZUMAN, L., BEALE, P., YU, J. Q., HUQ, F.|Anticancer Research recent issues|Labels: ovarian cancer

Currently used platinum drugs fail to provide long-term cure for ovarian cancer mainly because of acquired drug resistance. With the idea that the difference may translate into an altered spectrum of activity, monofunctional planaramineplatinum(II) complex tris(quinoline)monochloro-platinum chloride (coded as LH5) was synthesized and investigated for its activity against human ovarian A2780, cisplatin-resistant A2780 (A2780cisR) and ZD0473-resistnat A2780 (A2780ZD0473R) cancer cell lines alone and in combination with the phytochemicals capsaicin (Caps) and curcumin (Cur) as a function of concentration and sequence of administration. Cell viability was quantified using the MTT reduction assay, while combination was used as a quantitative measure of the combined drug action. LH5 is found to be more active than cisplatin (CS) against both resistant cell lines. Combination of LH5 with capsaicin showed synergism in all three cell lines, with the bolus being most synergistic. Lack of association between the levels of platinum accumulation and platinum–DNA with cytotoxicity can be seen to indicate that binding with DNA may not be the main determinant of activity of LH5. Greater activity of LH5 compared to cisplatin, especially against the resistant cell lines, indicates that the compound may have the potential for development as a novel anticancer drug and that its combination with phytochemicals can serve to further enhance drug efficacy.

Monday, May 16, 2016 6:39 PM|Yu-Hung Huang et al.|Labels: ovarian cancer

This retrospective study aimed to investigate the role that an RNA-binding protein, HuR, plays in the response of high-grade serous ovarian tumors to chemotherapeutics. We immunohistochemically stained sections of 31 surgically-debulked chemo-naïve ovarian tumors for HuR and scored the degree of HuR cytoplasmic staining. We found no correlation between HuR intracellular localization in tumor sections and progression free survival (PFS) of these patients, 29 of whom underwent second-line gemcitabine/platin combination therapy for recurrent disease. Ribonucleoprotein immunoprecipitation (RNP-IP) analysis of ovarian cancer cells in culture showed that cytoplasmic HuR increases deoxycytidine kinase (dCK), a metabolic enzyme that activates gemcitabine. The effects of carboplatin treatment on HuR and WEE1 (a mitotic inhibitor) expression, and on cell cycle kinetics, were also examined. Treatment of ovarian cancer cells with carboplatin results in increased HuR cytoplasmic expression and elevated WEE1 expression, arresting cell cycle G2/M transition. This may explain why HuR cytoplasmic localization in chemo-naïve tumors is not predictive of therapeutic response and PFS following second-line gemcitabine/platin combination therapy. These results suggest treatment of recurrent ovarian tumors with a combination of gemcitabine, carboplatin, and a WEE1 inhibitor may be potentially advantageous as compared to current clinical practices.

Thursday, April 28, 2016 9:59 AM|GADDUCCI, A., GUERRIERI, M. E.|Anticancer Research recent issues|Labels: PARP, ovarian cancer

Homologous recombination (HR) and base excision repair (BER) are two of the major DNA-repair pathways. The proteins encoded by breast-related cancer antigen (BRCA) and poly(adenosine diphosphate-ribose) polymerases (PARP) are involved in HR and BER, respectively. Tumors with HR deficiency, including those in BRCA mutation carriers, are sensitive to BER blockade via PARP inhibitors. These represent novel therapeutic tools for HR-deficient ovarian cancer, able to improve progression-free survival of women with recurrent, platinum-sensitive disease in response to recent platinum-based chemotherapy. More research is needed to assesses whether inhibitors of PARP have any role as maintenance treatment after first-line chemotherapy and as palliative treatment of platinum-resistant disease. Germline BRCA testing should be offered to all patients with ovarian cancer, regardless of age and family history. HR deficiency has been observed not only in germline BRCA mutation carriers, but also in patients with somatic mutations or epigenetic silencing of BRCA, and with loss of function of other genes. Half of all high-grade ovarian carcinomas are HR-deficient, and additional biological and clinical investigations are strongly warranted to identify patients with this subset of tumors.

We conducted a phase I study in ovarian cancer patients to evaluate the safety and immunogenicity of a synthetic unimolecular pentavalent carbohydrate vaccine (Globo-H, GM2, sTn, TF, and Tn) supported on a peptide backbone, conjugated to keyhole limpet haemocyanin (KLH), and mixed with immunological adjuvant QS-21. Twenty-four advanced-stage, poor-risk, first-remission ovarian cancer patients were enrolled from January 2011–Septermber 2013. Three dose levels were planned (25, 50, 100 mcg) with three cohorts of six patients each, with an additional 6-patient expansion cohort at the MTD. ELISA serologic IgM and IgG responses for each antigen was defined as positive response if antibody titers were ≥1:80 over the respective patient’s pre-vaccination serum. The study would be considered positive if at least four of 12 patients treated at the MTD showed immune responses for at least three of the five antigens. Twenty-four patients (median age, 54 years [range, 36–68]) were included in the safety analysis. Histology was high-grade serous in 22 patients (92%); 18 had stage III and six stage IV disease. The vaccine was well-tolerated at all doses, with no DLTs. At the highest treated dose, IgG and/or IgM responses were recorded against ≥3 antigens in 9/12 patients (75%), ≥4 in 7/12 (58%), and 5 in 3/12 (25%). With a median follow-up of 19 months (range, 2–39), 20 patients (83%) recurred and six (25%) died. The unimolecular pentavalent vaccine construct was shown to be safe and immunogenic. Such a construct greatly simplifies regulatory requirements and manufacturing, facilitates scalability, and provides adaptability.
CONCLUSIONSThe numerical improvement in the OS HR suggests that in Study 19, postprogression PARP inhibitor treatment had a confounding influence on the interim OS analysis for BRCAm patients. There is a degree of uncertainty due to the small sample size and the lack of data maturity. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Monday, March 28, 2016 5:30 AM|Current Cancer Therapy Reviews|MedWorm: Cancer Therapy|Comments|Labels: ovarian cancer
Ovarian cancer represents the second most common gynecologic cancer in the United States, with an estimated 22,000 new diagnoses and 14,000 deaths attributed in 2014 [1]. While the term loosely encompasses a large and varied assortment of malignancies, greater than 90% of ovarian cancers are epithelial carcinomas. Again within this category, there are a number of different histologic subtypes however, 60-70% of ovarian cancers are high-grade serous carcinomas. Overall, high-grade serous carcinomas account for 90% of deaths due to ovarian cancer. Early stage diagnosis has good prognosis with a predicted 5-year survival rate of over 90%. In contrast, late stage diagnosis has a 5-year survival of only 30%, a number which has not significantly changed over the past roughly half century [2]. Un...

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Tuesday, March 22, 2016 10:51 AM|McDowell, A., McCormick, T., Kuehl, T., Uddin, M., Afroze, S., Zawieja, D., Richard, T., Newell-Rogers, M.|Journal of Investigative Medicine recent issues|Labels: ovarian cancer
Objective

Cinobufotalin (CINO), a cardiotonic steroid (CTS) or bufadienolide, is extracted from the skin secretions of giant toads and is utilized in traditional Chinese medicine (Chan Su). CINO has been used as a cardiotonic, diuretic and a hemostatic agent. Our lab is familiar with CINO and has shown it to inhibit cytotrophoblast cells function. Recently, it has been shown that CINO also inhibits the lung cancer cell function, and has been further implicated in other disease processes. In the present study, we propose to pursue this potential application of CINO using ovarian tumor cell line SK-OV-3.

Study Design

We evaluated the in-vitro effect of CINO on ovarian cancer cell line SK-OV-3. Cells were treated with 0.1, 1, 5, and 10 µM CINO. Cell proliferation was measured using a CellTiter Assay (Promega), which is a colorimetric method for determining the number of viable cells. Cell migration was measured using a CytoSelect Assay (Cell Biolabs). Cell invasion was measured using a FluoroBlok Assay (BD). Cell viability was measure using a CellTiter Assay (Promega). Cell cycle progression was evaluated by a Cell Cycle Phase Determination Kit (Cayman Chemical) and apoptosis was evaluated by an Apoptotic Blebs Assay Kit (Cayman Chemical). Cell cycle arrest and apoptotic signaling was determined by fluorescence-activated cell sorting (FACS) analysis.

Results

CINO at ≥0.5 µM inhibited SKOV-3 cell proliferation, migration, and invasion (p<0.05). There was a higher (p<0.05) percentage of S phase cells in groups treated with CINO at 0.5 µM. CINO at ≥0.5 µM down regulated expression of PCNA and caused cell death.

Conclusion

This data demonstrates that CINO impairs SK-OV-3 cell function via cell cycle arrest and apoptotic signaling. These findings demonstrate the complex nature of this compound. Not only is CINO directly modulating the actions of the Na/K ATPase through classic mechanism of cardiotonic steroids, but is also directly influencing the nuclear expression of proteins involved in cell cycle progression and DNA repair. Additional investigational studies looking into the molecular pathways involved in altering cell cycle and entry into apoptosis are warranted.

In conclusion, we have shown CINO to impair SK-OV3 cell function via cell cycle arrest and apoptotic signaling and suggest that CINO might be further investigated as a novel anti-ovarian cancer agent.

Tuesday, March 22, 2016 10:51 AM|Afroze, S., Zawieja, D., Tobin, R., Peddaboina, C., Newell-Rogers, M., McDowell, A., McCormick, T., Kuehl, T., Uddin, M.|Journal of Investigative Medicine recent issues|Labels: ovarian cancer
Objective

Cinobufotalin (CINO), a cardiotonic steroid (CTS) or bufadienolide, is extracted from the skin secretions of the traditional Chinese medicine giant toads (Chan su). CINO has been used as a cardiotonic, diuretic and a hemostatic agent. Previously we have shown that CINO inhibits the cytotrophoblast cell function. Recently other study has shown that CINO inhibits A549, a lung cancer cell function. In this study, we assessed the effect of CINO on three different ovarian cancer cell lines; SK-OV-3, CRL-1978 and CRL-11731 to confirm whether the effect of CINO is cell specific.

Study Design

We evaluated the effect of CINO on three ovarian cancer cells SK-OV-3, CRL-1978, and CRL-11731 function in vitro. Each Cell lines were treated with different concentrations of CINO (0.1, 1, 5 and 10 µM). For each cell line cell proliferation, migration and invasion were measured by using a CellTiter Assay (Promega), Cytoselect Assay (Cell Biolabs) and by using a FluoroBlock Assay (BD) respectively. Proliferating Cell Nuclear Antigen (PCNA) was also evaluated in cell lysates of CINO treated these 3 ovarian cancer cells by western blot analysis. Cell Cycle arrest and Cell viability were determined by fluorescence-activated cell sorting (FACS) analysis. We also performed Annexin V staining on CINO treated these 3 ovarian cancer cell lines by immunofluorescence to evaluate the pro-apoptotic protein expression. In addition mitochondrial membrane potential has also been measured for all these 3 ovarian cell lines after CINO treatment using MMP kit, by FACS analysis.

Results

Concentration of CINO at 0.5 µM inhibit SK-OV-3, CRL-1978, and CRL-11731 ovarian cancer cells proliferation, migration and invasion without cell death and loss of cell viability but cell viability differs for each cell line. Each cell lines differ in response to CINO doses for PCNA expression as well as Annexin V pro-apoptotic protein expression. CINO decreases mitochondrial membrane potential for SK-OV-3 but for CRL-1978 and CRL-11731 increases in response to CINO treatment.

Conclusion

CINO is cell specific, as each cancer cell line responds differently. These data demonstrate that the mode of action of CINO is different on these 3 types of ovarian cancer cells.

Saturday, March 19, 2016 10:51 AM|Oncotarget|MedWorm: Cancer Therapy|Comments|Labels: ovarian cancer
Authors: Tang J, Wang J, Fan L, Li X, Liu N, Luo W, Wang J, Wang Y, Wang Y Abstract Vasculogenic minicry (VM), an alternative blood supply modality except to endothelial cells-mediated vascular network, is a potential therapeutic target for ovarian cancer due to VM correlated with poor prognosis in ovarian cancer patients. Accelerated extracellular matrix (ECM) degradation is prerequisite for VM formation induced by epithelial-mesenchymal transition (EMT). Previous reports demonstrate uPA has ability to degrade ECM thereby promoting tumor angiogenesis. Also, exogenous cRGD sequence enables to modulate uPA expression, attenuate EMT and suppress endothelial-lined channels. Till now, the correlation of uPA and VM formation and the effect of exogenous cRGD on VM formation remain unknow...
Sunday, February 14, 2016 4:00 PM|Oncology (Williston Park, N.Y.)|MedWorm: Transitional Cell Carcinoma|Comments|Labels: ovarian cancer
Authors: Ramalingam P Abstract Epithelial ovarian cancer comprises a heterogeneous group of tumors. The four most common subtypes are serous, endometrioid, clear cell, and mucinous carcinoma. Less common are transitional cell tumors, including transitional cell carcinoma and malignant Brenner tumor. While in the past these subtypes were grouped together and designated as epithelial ovarian tumors, these tumor types are now known to be separate entities with distinct clinical and biologic behaviors. From a therapeutic standpoint, current regimens employ standard chemotherapy based on stage and grade rather than histotype. However, this landscape may change in the era of personalized therapy, given that most subtypes (with the exception of high-grade serous carcinoma) are relatively ...
Wednesday, January 13, 2016 4:00 PM|Cancer Research|MedWorm: Cancer Therapy|Comments|Labels: ovarian cancer
Loss of function mutation of the epigenetic modulator ARID1A, a component of SWI/SNF chromatin remodeling complex, occurs in a number of cancers most notably ovarian. ARID1A is mutated in up to 60% and 30% of clear cell and endometrioid ovarian cancers, respectively. However, there currently is no effective therapy that targets ARID1A-deficient human cancers. Here we show ARID1A-deficient ovarian cancer cells are selectively sensitive to inhibition of EZH2's methyltransferase activity. EZH2 is the catalytic subunit of the polycomb repressor complex 2, which represses gene expression by generating tri-methylation epigenetic mark on lysine 27 of histone H3 (H3K27Me3). Utilizing a library of small molecules against epigenetic targets, we identified an EZH2 small molecule inhibitor that select...
Conclusions: The development of a new PARPi combination therapy with panobinostat has immediate prospects for rapid translation to the clinic and great potential for improving clinical outcomes for non-BRCAness, chemoresistant ovarian cancer.Citation Format: Andrew J. Wilson, Jeanette Saskowski, Dineo Khabele. The histone deacetylase inhibitor panobinostat sensitizes cyclin E-amplified ovarian cancer cells to poly ADP ribose polymerase inhibitors via E2F1 downregulation.. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr B37. (Source: Cancer Research)

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Wednesday, January 13, 2016 4:00 PM|Cancer Research|MedWorm: Cancer Therapy|Comments|Labels: ovarian cancer
DNA methyltransferase inhibitors (DNMTis) upregulate immune attraction, including the interferon response, in solid tumors. We now define viral defense signaling as one mechanism for this. In epithelial ovarian cancer cells DNMTis upregulate viral defense by cytosolic sensing of double-stranded RNA (dsRNA), triggering a Type I Interferon response, upregulation of downstream interferon response genes, and increased apoptosis. Knockdown of the dsRNA sensors TLR3 and MAVS and inhibition of the interferon alpha/beta receptor blunt the DNMTi induced dsRNA response. DNMTis cause apoptosis of cancer cells, which is partially rescued by inhibiting the interferon alpha/beta receptor. We observe upregulation and demethylation of hypermethylated endogenous retroviruses (ERVs) and overexpression of in...
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments
Conclusion. There are generally good correlation between transcriptome expression based molecular pathology and histopathology; the molecular pathology of PDXs are generally similar to that of human's, not so to human cell lines.References1. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513, 202-209 (2014).2. Hoshida, Y., et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer research 69, 7385-7392 (2009).3. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061-1068 (2008).4. Ge, L., et al. Integrated analysis of gene expression profile and genetic variations associated with ovarian cancer. European review for medical and pharmacological scienc...

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Conclusions: TR using clinical samples from patients with ovarian cancer demonstrated that KHK2805 may be a promising novel anti-FOLR1 ovarian therapeutic agent with a potent antitumor activity.Citation Format: Kaito Nihira, Munetoshi Ando, Keiko Nagata, Maiko Adachi, Yui Suzuki, Yutaka Kanda, Takeshi Oshima, Ken-ichiro Nan-ya, Masanori Hiura, Toshihiko Ishii, Ryuichiro Nakai, Takeshi Takahashi. A novel anti-FOLR1 antibody developed with AccretaMab® technology, KHK2805, exhibits potent anti-cancer activity against ovarian cancer samples with the FOLR1 expression. [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 C124. (S...

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Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ovarian cancer
Conclusion: Combination therapy efficacy of IMGN853 with Bev was substantially more than additive in multiple models of platinum resistant EOC. Combination IMGN853 + PLD is more efficacious than either monotherapy and combination IMGN853 + carboplatin is more efficacious than carboplatin + paclitaxel in the models studied. Addition of Bev to the carboplatin + IMGN853 combination further enhanced activity. Studies to understand the mechanism(s) responsible for the enhanced combination activity are under way. The efficacy observed in these models suggests that IMGN853 in combination with PLD, or Bev and/or carboplatin may be promising regimens to evaluate in clinical trials of EOC both in the relapsed and upfront settings. A phase1b clinical study assessing doublet combinations of IMGN853 wi...

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