A major impediment to improving survival of women witin ovarian cancer is the development of resistance to current therapies. Chemoresistance, whether intrinsic or acquired, is likely determined by genetic or epigenetic elements that influence the biology of the tumor. There are two strong arguments for an important role for epigenetic alterations in the heterogeneity of tumor response to therapy. Firstly, cancer is both a genetic and epigenetic disease. Secondly, induction of resistance with brief drug exposure can be rapid implicating the highly plastic nature of epigenetic marks. The DNA damage response coordinated by BRCA1, BRCA2 and additional genes in the Homologous Recombination (HR) pathway, such as PALB2, may make BRCA/HR pathway impaired ovarian tumors more susceptible to standard platinum-based therapy and, in particular, to drugs that further impair DNA repair, such as poly(ADP-ribose) polymerase 1 (PARP) inhibitors. While the vast majority of ovarian cancer is sporadic the presence of methylation of BRCAl and the recently identified methylation of PALB2 may impact chemoresponse through transcriptional silencing of these BRCA/HR pathway genes. We plan to interrogate our ovarian cancer methylome data and FCCC-PENN and national tumor repositries to determine tlie incidence of gene met/tylation-based impairment of the BRCA/HR pathway in sporadic ovarian cancer. We wiii then determine if the methylation status of BRCA1/HR pathway genes can predict both overall response and duration ofreponse to standard carboplatin therapy in patients with ovarian cancer. We will use the extent of cytoreduction as a surrogate for chemoreponse since this is the strongest indicator of clinical outcome after stage and wiii allow us to rapidly obtain the numbers of tumor necessary for statistical power. We will validate our findings in independent tumor cohorts banked from clinical trials by the Gynecological Oncology Group (GOG). If results warrant, by the beginning of the third year of funding we will initiate an exploratory clinical trial of a PARP-inhlbitor in ovarian cancer to guide the development of multl-lnstitutlonal Inter-SPORE clinical trial. We will further develop our assay for detection of gene methylation in blood as a non-invasive predictive test for selecting therapy at time of recurrence. The long-term goal of this project is to translate our knowledge in epigenetics into significant advances in the predictive classification and treatment of ovarian cancer.

Public Health Relevance

Early data has demonstrated significant activity of PARP inhibitors in women with germline mutations in BRCA genes likely due to defects in homologous recombination (HR) and DNA repair. A subset of sporadic ovarian cancers demonstrate inactivation of BRCA1 and/or other genes by methylation which should impair HR. These epigenetic marks may serve as a potent predictive marker for both ongoing platinum sensitivity and sensitivity to PARP inhibitors. Detection of methylation in the serum of women could facilitate the rapid and non-invasive selection of women most likely to benefit from these therapies. PROJECT/

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
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Fox Chase Cancer Center
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Yang, Lu; Zhang, Youyou; Shan, Weiwei et al. (2017) Repression of BET activity sensitizes homologous recombination-proficient cancers to PARP inhibition. Sci Transl Med 9:
Beck, Tim N; Smith, Chad H; Flieder, Douglas B et al. (2017) Head and neck squamous cell carcinoma: Ambiguous human papillomavirus status, elevated p16, and deleted retinoblastoma 1. Head Neck 39:E34-E39
Skates, Steven J; Greene, Mark H; Buys, Saundra S et al. (2017) Early Detection of Ovarian Cancer using the Risk of Ovarian Cancer Algorithm with Frequent CA125 Testing in Women at Increased Familial Risk - Combined Results from Two Screening Trials. Clin Cancer Res 23:3628-3637
Zhang, Dongmei; Zhang, Gao; Hu, Xiaowen et al. (2017) Oncogenic RAS Regulates Long Noncoding RNA Orilnc1 in Human Cancer. Cancer Res 77:3745-3757
Rebbeck, Timothy R; Friebel, Tara M; Mitra, Nandita et al. (2016) Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women. Breast Cancer Res 18:112
Zhong, Xiaomin; Zheng, Lan; Shen, Jianfeng et al. (2016) Suppression of MicroRNA 200 Family Expression by Oncogenic KRAS Activation Promotes Cell Survival and Epithelial-Mesenchymal Transition in KRAS-Driven Cancer. Mol Cell Biol 36:2742-2754
Beck, Tim N; Golemis, Erica A (2016) Genomic insights into head and neck cancer. Cancers Head Neck 1:
Zhang, Youyou; Feng, Yi; Hu, Zhongyi et al. (2016) Characterization of Long Noncoding RNA-Associated Proteins by RNA-Immunoprecipitation. Methods Mol Biol 1402:19-26
Prudnikova, T Y; Villamar-Cruz, O; Rawat, S J et al. (2016) Effects of p21-activated kinase 1 inhibition on 11q13-amplified ovarian cancer cells. Oncogene 35:2178-85
Beck, Tim N; Georgopoulos, Rachel; Shagisultanova, Elena I et al. (2016) EGFR and RB1 as Dual Biomarkers in HPV-Negative Head and Neck Cancer. Mol Cancer Ther 15:2486-2497

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