Methylation and Mutation Assay to Personalize PARP Inhibitor Therapy

甲基化和突变检测以个性化 PARP 抑制剂治疗

基本信息

批准号：
10028143
负责人：
ELIZABETH MARY SWISHER
金额：
$ 45.95万
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：
2020-09-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10028143
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 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/antagonist methylation testing mutation assay neoplastic predicting response predictive marker promoter recombinational repair repaired response therapeutic target

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 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.

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，我们的方法是将高吞吐量和定量甲基化测定以及关键同源重组基因的突变分析。我们将精益求精我们的检测使用来自储存的肿瘤组织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 个大型 3I 期随机对照试验的样本测试这些测定（RCT）在 OC 中采用三种不同的 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以及甲基化和突变组合检测 (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：在卵巢复发的随机对照试验中验证 MMA 作为 PARPi 反应的预测因子癌。目标 3：在 3 项主要治疗随机对照试验中验证 MMA 作为 PARPi 反应的预测因子先进的OC。