Methylation and Mutation Assay to Personalize PARP Inhibitor Therapy

项目总结/摘要 目前提案的总体目标是开发一种临床上有用的PARP抑制剂（PARPi）预测因子 敏感性/耐受性，避免毒性和患者不太可能获益的成本。我们假设 在治疗开始前立即进行的联合突变和甲基化分析将提供一个 PARPi反应的有用预测因子。为了验证这一假设，我们的方法是将高通量和联合收割机结合起来 用关键同源重组基因的突变分析进行定量甲基化测定。我们将完善 我们的检测使用了来自一个肿瘤组织库和福尔马林固定石蜡包埋（FFPE）的肿瘤样本。 2期PARPi试验，然后使用来自4项大型III期随机对照试验的样本对这些测定进行测试 (RCT)在OC中，使用三种不同PARPi。 我们提出三个具体目标： 目的1：建立一种临床分级、定量甲基化检测方法及甲基化和突变联合检测方法 (MMA)确定对PARP抑制剂有最佳反应的BRCA野生型癌症。 目的2：在复发性卵巢癌的随机对照试验中，将ARMMA作为PARPi反应的预测因子 carcinoma. 目的3：在3项主要治疗的随机对照试验中，将ARMMA作为PARPi应答的预测因子 先进的OC

PROJECT SUMMARY/ABSTRACT The overall goal of the current proposal is to develop a clinically useful predictor of PARP inhibitor (PARPi) sensitivity/resistance to spare toxicities and cost for patients unlikely to derive benefit. Our hypothesis is that a combined mutation and methylation analysis performed immediately before initiation of therapy will provide a useful predictor of PARPi response. To test this hypothesis, our approach is to combine a high throughput and quantitative methylation assay with mutational analysis of key homologous recombination genes. We will refine our assay using banked tumor tissues and formalin fixed paraffin embedded (FFPE) neoplastic samples from a phase 2 PARPi trial, then test these assays using samples from 4 large phase 3I randomized controlled trials (RCT) in OC that employ three different PARPi. We propose three specific aims: Aim 1: Develop a clinical grade, quantitative methylation assay and a combined methylation and mutation assay (MMA) to define those BRCA wildtype cancers with best response to PARP inhibitors. Aim 2: Validate MMA as a predictor of PARPi response in a randomized controlled trial of recurrent ovarian carcinoma. Aim 3: Validate MMA as a predictor of PARPi response in 3 randomized controlled trials for primary treatment of advanced OC.