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：
10670755
负责人：
ELIZABETH MARY SWISHER
金额：
$ 58.53万
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/10670755
关键词：
Alleles Antineoplastic Agents BRCA mutations BRCA1 gene BRCA2 gene Biological Assay Cells Clinical Collaborations DNA Double Strand Break 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) Polymerase Inhibitor RAD51C gene Randomized, Controlled Trials Recurrence Resistance S phase Sampling Solid Somatic Mutation Specimen Testing Therapeutic 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 gene repair homologous recombination improved 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.

项目摘要/摘要当前建议的总体目标是开发PARP抑制剂（PARPI）的临床上有用的预测指标对备用毒性的敏感性/抵抗力和对患者的成本不太可能获得收益。我们的假设是在开始治疗之前立即进行的突变和甲基化分析将提供 PARPI响应的有用预测指标。为了检验这一假设，我们的方法是完成关键人力资源基因的高通量和定量甲基化测定福尔马林组织固定石蜡嵌入了II期PARPI试验的肿瘤样品，然后使用来自OC和BC中4个大型III随机对照试验（RCT）的样品测试这些测定采用三个不同的parpi。我们提出了三个具体目标：目标1：开发临床等级，定量甲基化测定法和甲基化合并突变测定（MMA）定义那些对PARP抑制剂的反应最佳的BRCA野生型癌症。目标2：验证HRR突变和甲基化测定（MMA）作为PARPI的预测因子在2个复发性乳腺癌和卵巢癌的随机对照试验中的反应。 AIM 3：在2个随机对照试验中验证MMA作为PARPI响应的预测指标治疗晚期卵巢癌。这些研究将共同洞悉PARPI敏感性的机制，同时开发临床可以适用于其他癌症类型的乳腺癌和卵巢癌的预测因子。这些研究将领导更精确地治疗PARP抑制剂，降低毒性和成本，同时最大化患者益处。