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

项目摘要 胰腺导管腺癌是美国癌症相关死亡的第三大原因。 各州。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，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，如ATM和CHEK2。一个 BRCA1和BRCA2以及其他DDR基因突变的PDAC患者亚群可能具有持久性 肿瘤对聚(ADP-核糖)聚合酶(PARP)抑制剂的反应；然而，最理想的生物标记物没有 被确定为预测哪些患者将从这些疗法中受益。此外，联合治疗 超越单剂PARP抑制的计划尚未定义。这项建议汇集了一个 由杰出的实验室、翻译和临床研究人员组成的团队：(1)定义最佳基因组和 识别患有DDR缺陷的PDAC患者的功能策略；(2)进行治疗试验，以确定 从PARP抑制中获益最大的患者以及识别从头和获得性的机制 耐药性；以及(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 提议，我们将定义可扩展的基因组和功能分析，包括新的突变特征，新的 DNA复制叉稳定性分析和RAD51病灶的免疫组织化学分析，可以识别患者 存在心率缺乏(HRD)或其他DDR缺陷的PDAC，因此临床医生可以有效地选择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人员发起的阶段 2项临床试验，以确定PARP抑制剂niraparib对DDR突变PDAC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 使用新型患者衍生器官系模型治疗DDR缺陷PDAC患者的策略 在DDR缺乏和熟练的情况下，PARP抑制剂的敏感性和耐药性。利用独一无二的 基因组分析，创新的DDR缺陷分析，新的患者衍生模型，大量的临床 PDAC患者，多学科团队科学方法，并与生物谱系和 病理学核心(核心B)和生物统计和生物信息学核心(核心C)，这项提案将提供(1) 明确的生物标志物策略，临床医生可以通过这些策略识别患有DDR缺陷的PDAC患者，(2)数据 DDR缺陷的PDAC对PARP抑制的反应性，(3)对抗性的新机制见解 在PDAC中抑制PARP的机制，以及(4)下一代PARP抑制的组合策略 PDAC临床试验。通过这些研究，我们的目标是在治疗策略上做出有意义的改进 对于患有DDR缺乏症的PDAC患者的这一重要亚群。

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.