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: 10670782
• 负责人: Brian Matthew Wolpin
• 金额: $ 33.11万
• 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/10670782
• 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; Combined Modality Therapy; 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; PALB2 gene; 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) Polymerase Inhibitor; Poly(ADP-ribose) Polymerases; Pre-Clinical Model; Research Personnel; Resistance; Resources; Science; Somatic Mutation; Specimen; Testing; Time; Tissues; United States; cohort; comparative efficacy; ds-DNA; early experience; effective therapy; efficacy evaluation; exome; gene repair; genomic signature; homologous recombination; improved; inhibitor; 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.

项目摘要 胰腺导管腺癌（PDAC）是美国癌症相关死亡的第三大原因。 States.高达20%的PDAC患者在涉及双链DNA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BRCA 1， BRCA 2和PALB 2，以及参与DNA损伤反应的基因，如ATM和CHEK 2。一 具有BRCA 1和BRCA 2以及其他DDR基因突变的PDAC患者的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， 已经被确定来预测哪些患者将从这些治疗中受益。此外，联合治疗 超越单剂PARP抑制的程序还没有定义。该提案汇集了一个 由杰出的实验室、翻译和临床研究人员组成的团队：（1）确定最佳的基因组和 识别DDR缺陷的PDAC患者的功能策略;（2）进行治疗试验，以识别 从PARP抑制中获益最大的患者，并确定新发和获得性 耐药性;和（3）为未来的临床试验定义新的联合治疗策略。目标1 建议，我们将定义可扩展的基因组和功能测定，包括新的突变签名，新的 DNA复制叉稳定性测定和RAD 51病灶的免疫组织化学测定， 具有HR缺陷（HRD）或其他DDR缺陷的PDAC，以便临床医生可以有效地选择PDAC 最有可能受益于靶向治疗的患者。在目标2中，我们将执行一个触发器启动的阶段， 2项确定PARP抑制剂Niraparib在DDR突变型PDAC中的疗效的临床试验，并将确定 敏感性的决定因素和获得性抗性的机制。在目标3中，我们将确定 使用新的患者来源的类器官系治疗DDR缺陷型PDAC患者的治疗策略， DDR缺陷和熟练情况下的PARP抑制剂敏感性和耐药性。利用独特的 基因组分析，创新的DDR缺陷检测，新的患者衍生模型，大量的临床研究， PDAC患者，多学科团队科学方法，以及与生物标本和 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），本提案将提供（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） DDR-deficient PDAC对PARP抑制的反应性，（3）对抗性的新机制见解 PDAC中PARP抑制的机制，以及（4）在下一代中进行测试的组合策略 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。 对于这个重要的PDAC患者亚群，他们有DDR缺陷。