Combined Methylation and Mutation to Predict Response to PARP Inhibitors

结合甲基化和突变来预测对 PARP 抑制剂的反应

基本信息

批准号：
10378133
负责人：
ELIZABETH MARY SWISHER
金额：
$ 59.67万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10378133
关键词：
Alleles Antineoplastic Agents Archives BRCA1 gene BRCA2 Mutation BRCA2 gene Biological Assay Cells Clinical Collaborations DNA Repair DNA Repair Pathway Decision Making Development Down-Regulation Drug usage Formalin G2 Phase Gene Expression Regulation Genes Goals Gynecologic Oncology Group Laboratories Maintenance Maintenance Therapy Malignant Neoplasms Malignant neoplasm of ovary Mammalian Oviducts Medicine Methylation Mutation Mutation Analysis Nonhomologous DNA End Joining Oncology Open Reading Frames Ovarian Carcinoma Paraffin Embedding Patient Selection Patients Peritoneal Phase Platinum Poly(ADP-ribose) Polymerases RAD51C gene Randomized Controlled Trials Recurrence Resistance S phase Sampling Solid Somatic Mutation Specimen Testing Therapeutic Time Toxic effect Tumor Bank Tumor Tissue Work cancer cell cancer therapy cancer type cell killing chemotherapy clinical predictors companion diagnostics cost cost effective diagnostic biomarker ds-DNA gene repair homologous recombination improved inhibitor insight malignant breast neoplasm methylation testing mutation assay neoplastic predicting response predictive marker promoter recombinational repair repaired response therapeutic target triple-negative invasive breast carcinoma

项目摘要

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.

项目概要/摘要当前提案的总体目标是开发一种临床上有用的 PARP 抑制剂 (PARPi) 预测因子对不太可能受益的患者的毒性和成本的敏感性/抵抗力。我们的假设是在开始治疗前立即进行的突变和甲基化组合分析将提供 PARPi 反应的有用预测因子。为了检验这个假设，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测定，并使用库中的数据完善我们的测定来自 II 期 PARPi 试验的肿瘤组织福尔马林固定石蜡包埋 (FFPE) 肿瘤样本，然后使用来自 OC 和 BC 的 4 个大型 III 期随机对照试验 (RCT) 的样本来测试这些测定采用三种不同的 PARPi。我们提出三个具体目标：目标 1：开发临床级定量甲基化检测方法以及甲基化和甲基化联合检测方法突变测定 (MMA) 来定义对 PARP 抑制剂具有最佳反应的 BRCA 野生型癌症。目标 2：验证 HRR 突变和甲基化联合测定 (MMA) 作为 PARPi 的预测因子两项针对复发性乳腺癌和卵巢癌的随机对照试验的反应。目标 3：在 2 项原发性随机对照试验中验证 MMA 作为 PARPi 反应的预测因子治疗晚期卵巢癌。总之，这些研究将深入了解 PARPi 敏感性的机制，同时开发临床方法乳腺癌和卵巢癌的预测因子，也适用于其他癌症类型。这些研究将引导更精确地应用 PARP 抑制剂，降低毒性和成本，同时最大限度地提高患者的治疗效果益处。