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

• 批准号: 10405502
• 负责人: ELIZABETH MARY SWISHER
• 金额: $ 45.5万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405502
• 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; inhibitor therapy; methylation testing; mutation assay; neoplastic; predicting response; predictive marker; promoter; recombinational repair; repaired; response; therapeutic target

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，我们的方法是结合高通量和 定量甲基化测定法，对关键同源重组基因的突变分析。我们将完善 我们使用库肿瘤组织和福尔马林固定石蜡嵌入（FFPE）肿瘤样品的测定法 第2阶段PARPI试验，然后使用来自4个大型3i阶段随机对照试验的样品测试这些测定 （RCT）在OC中采用三种不同的PARPI。 我们提出了三个具体目标： AIM 1：开发临床等级，定量甲基化测定以及甲基化和突变测定法 （MMA）定义那些对PARP抑制剂的反应最佳的BRCA野生型癌。 AIM 2：在复发性卵巢的随机对照试验中验证MMA作为PARPI响应的预测指标 癌。 AIM 3：在3个随机对照试验中验证MMA作为PARPI响应的预测指标 高级OC。

项目成果

The role of aberrant DNA methylation in cancer initiation and clinical impacts.

• DOI: 10.1177/17588359231220511
• 发表时间: 2024
• 期刊: THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY
• 影响因子: 4.9
• 作者: Geissler, Franziska;Nesic, Ksenija;Kondrashova, Olga;Dobrovic, Alexander;Swisher, Elizabeth M.;Scott, Clare L.;J. Wakefield, Matthew
• 通讯作者: J. Wakefield, Matthew