Combined Methylation and Mutation to Predict Response to PARP Inhibitors

项目摘要/摘要 目前提案的总体目标是开发一种临床上有用的PARP抑制物(PARPI)预测因子 对不太可能受益的患者的额外毒性和成本的敏感性/抵抗力。我们的假设是一个 在治疗开始前立即进行的联合突变和甲基化分析将提供 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 对关键HR基因进行高通量和定量甲基化分析，并使用BANKED改进我们的分析 肿瘤组织福尔马林固定石蜡包埋(FFPE)肿瘤样本来自II期PARPI试验，然后 使用来自OC和BC的4个大型III期随机对照试验(RCT)的样本来测试这些分析 采用三种不同的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和甲基化联合检测方法 突变试验(MMA)以确定对PARP抑制剂反应最好的BRCA野生型癌症。 目的2：验证HRR突变和甲基化联合试验(MMA)作为预测PARPI的指标 复发性乳腺癌和卵巢癌的2个随机对照试验的反应。 目的3：在2个随机对照试验中验证MMA作为PARPI反应的预测因子 晚期卵巢癌的治疗。 总之，这些研究将提供对PARPI敏感性机制的洞察，同时开发一种临床 乳腺癌和卵巢癌的预测指标，这可能适用于其他癌症类型。这些研究将导致 更精确地应用PARP抑制剂，减少毒性和成本，同时最大限度地增加患者 利益。

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.