Gene Methylation Signatures for Predictive Classification of Response to Therapy

提高卵巢癌患者生存率的一个主要障碍是耐药性的发展 目前的治疗方法。化学抗性，无论是内在的还是获得的，可能是由遗传或 影响肿瘤生物学的表观遗传因素。有两个强有力的论点， 表观遗传学改变在肿瘤对治疗反应的异质性中的重要作用。首先，癌症是 遗传和表观遗传疾病第二，通过短暂的药物暴露诱导耐药性， 暗示了表观遗传标记的高度可塑性。DNA损伤反应由 BRCA 1、BRCA 2和同源异型增生（HR）途径中的其他基因，如PALB 2， 可能使BRCA/HR通路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散发性的，但卵巢癌基因甲基化的存在， BRCA 1和最近鉴定的PALB 2甲基化可能通过以下途径影响化学反应： 这些BRCA/HR途径基因的转录沉默。 我们计划询问我们的卵巢癌甲基化组数据和FCCC-PENN和国家肿瘤 基因库，以确定BRCA/HR途径的基因突变/突变型损伤的发生率， 散发性卵巢癌然后我们将确定BRCA 1/HR通路基因的甲基化状态是否 可以预测标准卡铂治疗的总体反应和反应持续时间， 卵巢癌我们将使用细胞减少的程度作为化学反应的替代，因为这是 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数量 这是统计力量所必需的。我们将在独立的肿瘤队列中验证我们的发现， 妇科肿瘤组（GOG）的临床试验。如果结果允许，在第三次会议开始时， 在一年的资金支持下，我们将启动一项PARP抑制剂在卵巢癌中的探索性临床试验， 多机构间孢子临床试验的开发。我们将进一步发展我们的检测方法， 血液中的基因甲基化作为复发时选择治疗的非侵入性预测测试。 该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 卵巢癌的预测分类和治疗。 相关性（参见说明）： 早期数据表明，PARP抑制剂在具有生殖系突变的女性中具有显著活性， BRCA基因可能是由于同源重组（HR）和DNA修复缺陷所致。的子集 散发性卵巢癌显示BRCA 1和/或其它基因通过甲基化失活， 这些表观遗传标记可能作为一个有效的预测标记， 铂敏感性和对PARP抑制剂的敏感性。女性血清甲基化检测 可以促进快速和非侵入性选择最有可能从这些治疗中受益的女性。 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/