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: 10456160
• 负责人: Brian Matthew Wolpin
• 金额: $ 36.64万
• 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/10456160
• 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; 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) 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; 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.

项目总结