Combined Methylation and Mutation to Predict Response to PARP Inhibitors

项目概要/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，我们的方法是完成一个 关键HR基因的高通量和定量甲基化测定，并使用库库 来自II期PARPi试验的福尔马林固定石蜡包埋（FFPE）肿瘤样本，然后 使用来自OC和BC中的4项大型III期随机对照试验（RCT）的样本对这些测定进行测试， 使用三种不同的PARPi。我们提出三个具体目标： 目的1：开发临床分级、定量甲基化测定和联合甲基化和 突变试验（MMA），以确定那些对PARP抑制剂有最佳反应的BRCA野生型癌症。 目的2：验证HRR突变和甲基化联合检测（MMA）可作为PARPi的预测指标 复发性乳腺癌和卵巢癌的2项随机对照试验中的缓解。 目的3：在2项随机对照试验中，将ARMMA作为PARPi缓解的预测因子，用于原发性 晚期卵巢癌的治疗 总之，这些研究将提供对PARPi敏感性机制的深入了解，同时开发临床治疗方案。 乳腺癌和卵巢癌的预测因子，这也适用于其他类型的癌症。这些研究将导致 PARP抑制剂的更精确的治疗应用，降低毒性和成本，同时最大限度地提高患者 效益

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 complete development of a high throughput and quantitative methylation assay for key HR genes and refine our assays using banked tumor tissues formalin fixed paraffin embedded (FFPE) neoplastic samples from phase II PARPi trials, then test these assays using samples from 4 large phase III randomized controlled trials (RCT) in OC and BC 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 the combined HRR mutation and methylation assay (MMA) as a predictor of PARPi response in 2 randomized controlled trials of recurrent breast and ovarian cancer. Aim 3: Validate MMA as a predictor of PARPi response in 2 randomized controlled trials for primary treatment of advanced ovarian cancer. Together, these studies will provide insight into mechanisms of PARPi sensitivity while developing a clinical predictor for both breast and ovarian cancer, which could apply to other cancer types. These studies will lead to more precise therapeutic application of PARP inhibitors, reducing toxicity and cost while maximizing patient benefit.