Gene Methylation Signatures for Predictive Classification of Response to Therapy

卵巢癌患者提高存活率的一个主要障碍是耐药性的产生。 到目前的治疗方法。化疗耐药性，无论是先天的还是后天的，很可能是由遗传或 影响肿瘤生物学的表观遗传因素。有两个强有力的理由支持 表观遗传学改变在肿瘤治疗反应异质性中的重要作用。首先，癌症是 既是一种遗传性疾病，也是一种表观遗传病。其次，通过短暂的药物暴露诱导耐药性可能是 迅速暗示了表观遗传标记的高度可塑性。DNA损伤反应由以下因素协调 BRCA1、BRCA2和同源重组(HR)途径中的附加基因，如PALB2、 可能使BRCA/HR途径受损的卵巢肿瘤对标准铂类药物更敏感 治疗，特别是进一步损害DNA修复的药物，如聚(ADP-核糖)聚合酶1 (PARP)抑制剂。虽然绝大多数卵巢癌是零星的，但甲基化的存在 BRCA1和最近发现的PALB2甲基化可能通过以下途径影响化学反应 这些BRCA/HR途径基因转录沉默。 我们计划询问我们的卵巢癌甲基组数据和fccc-Penn和国家肿瘤 一种用于检测人类BRCA/HR通路MET/甲基化损伤发生率的试剂库 散发性卵巢癌。然后我们将确定BRCA1/HR途径基因的甲基化状态 可以预测标准卡铂治疗的总有效率和持续时间 卵巢癌。我们将使用细胞减少的程度作为化疗反应的替代，因为这是 分期后临床结果的最强指标，将使我们能够快速获得肿瘤的数量 这是统计权力所必需的。我们将在独立的肿瘤队列中验证我们的发现 妇科肿瘤学小组(GOG)的临床试验。如果结果成立，在第三个月开始之前 我们将启动一项卵巢癌PARP抑制物的探索性临床试验，以指导 多机构间孢子临床试验进展。我们将进一步发展我们的检测方法 血液中基因甲基化的检测可作为复发时选择治疗方法的无创性预测试验。 这个项目的长期目标是将我们在表观遗传学方面的知识转化为在 卵巢癌的预测性分类和治疗。 相关性(请参阅说明)： 早期数据显示，在患有生殖系突变的女性中，PARP抑制剂具有显著的活性 BRCA基因可能是由于同源重组和DNA修复缺陷所致。的子集 散发性卵巢癌表现为BRCA1和/或其他基因甲基化失活 应该会损害人力资源。这些表观遗传标记可以作为正在进行的 铂敏感性和对PARP抑制剂的敏感性。女性血清甲基化的检测 可以促进快速和非侵入性地选择最有可能从这些疗法中受益的妇女。 项目/

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. RELEVANCE (See instructions): 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/