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.
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/
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