Project 3 - Improving Therapy for DNA-Damage Deficient Pancreatic Adenocarcinoma

项目 3 - 改善 DNA 损伤缺陷型胰腺癌的治疗

• 批准号: 10005199
• 负责人: Brian Matthew Wolpin
• 金额: $ 24.59万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005199
• 关键词: BRCA1 gene; BRCA2 gene; Bioinformatics; Biological Assay; Biological Markers; Biometry; Biopsy; CHEK1 gene; CHEK2 gene; Cancer Center; Cancer Etiology; Cessation of life; Clinic; Clinical; Clinical Investigator; Clinical Trials; Collaborations; DNA Damage; DNA Repair; DNA replication fork; DNA sequencing; Data; Defect; Drug Combinations; Formalin; Future; Gene Mutation; Genes; Genomics; Germ-Line Mutation; Impairment; In Vitro; Investigation; Laboratories; Malignant neoplasm of gastrointestinal tract; Modeling; Mutation; Organoids; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Paraffin Embedding; Pathogenicity; Pathology; Pathway interactions; Patient Care; Patients; Phase I Clinical Trials; Phase II Clinical Trials; Platinum Compounds; Poly(ADP-ribose) Polymerases; Pre-Clinical Model; Research Personnel; Resistance; Resources; Science; Somatic Mutation; Specimen; Testing; Time; Tissues; United States; base; cohort; comparative efficacy; ds-DNA; early experience; effective therapy; exome; gene repair; genomic signature; homologous recombination; improved; inhibitor/antagonist; innovation; insight; multidisciplinary; mutant; next generation; novel; novel drug class; patient population; patient subsets; pre-clinical; preclinical study; predicting response; recombinational repair; resistance mechanism; response; targeted treatment; translational scientist; treatment program; treatment response; treatment strategy; treatment trial; tumor; tumor progression; whole genome

Project Summary Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States. Up to 20% of PDAC patients harbor germline or somatic mutations in genes involved in double-strand DNA damage repair (DDR), including the homologous recombination (HR) repair pathway genes BRCA1, BRCA2 and PALB2, as well as genes involved in the DNA damage response, such as ATM and CHEK2. A subset of PDAC patients with mutations in BRCA1 and BRCA2, as well as other DDR genes, may have durable tumor responses to poly(ADP-ribose) polymerase (PARP) inhibitors; however, the optimal biomarkers have not been identified to predict which patients will benefit from these therapies. Furthermore, combination treatment programs to move beyond single-agent PARP inhibition are not yet defined. This proposal brings together a team of distinguished laboratory, translational and clinical investigators to: (1) define optimal genomic and functional strategies for identifying PDAC patients with DDR deficiency; (2) conduct treatment trials to identify the patients with greatest benefit from PARP inhibition and to identify mechanisms of de novo and acquired resistance; and (3) to define novel combination treatment strategies for future clinical trials. In Aim 1 of this proposal, we will define scalable genomic and functional assays, including novel mutational signatures, a novel DNA replication fork stability assay, and immunohistochemical assays for RAD51 foci, that identify patients with PDAC harboring HR deficiency (HRD) or other DDR defects, so that clinicians can efficiently select PDAC patients most likely to benefit from targeted therapies. In Aim 2, we will perform an investigator-initiated, phase 2 clinical trial to determine the efficacy of the PARP inhibitor niraparib in DDR-mutant PDAC and will identify determinants of sensitivity and mechanisms of acquired resistance. In Aim 3, we will identify combination treatment strategies for patients with DDR-deficient PDAC using novel patient-derived organoid lines that model PARP inhibitor sensitivity and resistance in both DDR deficient and proficient contexts. Leveraging unique genomic analyses, innovative DDR deficiency assays, novel patient-derived models, a large clinical volume of PDAC patients, a multi-disciplinary team-science approach, and close collaboration with the Biospecimens and Pathology Core (Core B) and the Biostatistics and Bioinformatics Core (Core C), this proposal will deliver (1) clear biomarker strategies by which clinicians can identify patients with DDR-deficient PDAC, (2) data for the responsiveness of DDR-deficient PDAC to PARP inhibition, (3) new mechanistic insights into resistance mechanisms to PARP inhibition in PDAC, and (4) combination strategies for testing in the next generation of PDAC clinical trials. Through these studies, we aim to make meaningful improvements in treatment strategies for this important subset of PDAC patients who harbor DDR deficiency.

项目概要 胰腺导管腺癌 (PDAC) 是美国癌症相关死亡的第三大原因 国家。高达 20% 的 PDAC 患者在涉及双链的基因中存在种系或体细胞突变 DNA损伤修复（DDR），包括同源重组（HR）修复途径基因BRCA1， BRCA2 和 PALB2，以及参与 DNA 损伤反应的基因，例如 ATM 和 CHEK2。一个 具有 BRCA1 和 BRCA2 以及其他 DDR 基因突变的 PDAC 患者子集可能具有持久的 肿瘤对聚（ADP-核糖）聚合酶（PARP）抑制剂的反应；然而，最佳的生物标志物还没有 已被确定可以预测哪些患者将从这些疗法中受益。此外，联合治疗 超越单药 PARP 抑制的方案尚未确定。该提案汇集了 由杰出的实验室、转化和临床研究人员组成的团队：(1) 定义最佳基因组和 识别具有 DDR 缺陷的 PDAC 患者的功能策略； (2) 进行治疗试验以确定 患者从 PARP 抑制中受益最大，并确定从头和获得性的机制 反抗; (3) 为未来的临床试验确定新的联合治疗策略。在这个目标1中 提案中，我们将定义可扩展的基因组和功能测定，包括新的突变特征、新的 DNA 复制叉稳定性测定和 RAD51 病灶的免疫组织化学测定，可识别患有以下疾病的患者 PDAC存在HR缺陷（HRD）或其他DDR缺陷，以便临床医生有效选择PDAC 最有可能从靶向治疗中受益的患者。在目标 2 中，我们将执行一个由研究者发起的阶段 2 项临床试验，以确定 PARP 抑制剂 niraparib 在 DDR 突变型 PDAC 中的疗效，并将确定 敏感性的决定因素和获得性耐药的机制。在目标 3 中，我们将确定组合 使用新型患者衍生类器官系对 DDR 缺陷型 PDAC 患者进行建模的治疗策略 DDR 缺乏和熟练环境中的 PARP 抑制剂敏感性和耐药性。凭借独特的 基因组分析、创新的 DDR 缺陷测定、新颖的患者衍生模型、大量临床数据 PDAC 患者、多学科团队科学方法以及与生物样本和 病理学核心（核心 B）和生物统计学和生物信息学核心（核心 C），该提案将提供 (1) 明确的生物标志物策略，临床医生可以通过该策略识别 DDR 缺陷型 PDAC 患者，(2) 数据 DDR 缺陷的 PDAC 对 PARP 抑制的反应，(3) 对耐药性的新机制见解 PDAC 中 PARP 抑制的机制，以及（4）用于下一代测试的组合策略 PDAC 临床试验。通过这些研究，我们的目标是对治疗策略做出有意义的改进 对于患有 DDR 缺陷的这一重要 PDAC 患者亚群。