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.
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States. Up to 20% of PDAC patients harbor mutations in genes responsible for double-strand DNA damage repair (DDR), and these defects may unveil vulnerabilities to treatment with a novel class of drugs called PARP inhibitors. This proposal brings together a team of distinguished laboratory, translational and clinical investigators to define optimal strategies for identifying PDAC patients with DDR deficiency and to conduct innovative PARP inhibitor treatment trials to improve care for these patients.
| Danai, Laura V; Babic, Ana; Rosenthal, Michael H et al. (2018) Altered exocrine function can drive adipose wasting in early pancreatic cancer. Nature 558:600-604 |
| Grasso, Catherine S; Giannakis, Marios; Wells, Daniel K et al. (2018) Genetic Mechanisms of Immune Evasion in Colorectal Cancer. Cancer Discov 8:730-749 |
| Corcoran, Ryan B; André, Thierry; Atreya, Chloe E et al. (2018) Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAFV600E-Mutant Colorectal Cancer. Cancer Discov 8:428-443 |
| Song, Mingyang; Wu, Kana; Meyerhardt, Jeffrey A et al. (2018) Fiber Intake and Survival After Colorectal Cancer Diagnosis. JAMA Oncol 4:71-79 |
| Babic, A; Schnure, N; Neupane, N P et al. (2018) Plasma inflammatory cytokines and survival of pancreatic cancer patients. Clin Transl Gastroenterol 9:145 |
| Lopes-Ramos, Camila M; Kuijjer, Marieke L; Ogino, Shuji et al. (2018) Gene Regulatory Network Analysis Identifies Sex-Linked Differences in Colon Cancer Drug Metabolism. Cancer Res 78:5538-5547 |
| Van Blarigan, Erin L; Ou, Fang-Shu; Niedzwiecki, Donna et al. (2018) Dietary Fat Intake after Colon Cancer Diagnosis in Relation to Cancer Recurrence and Survival: CALGB 89803 (Alliance). Cancer Epidemiol Biomarkers Prev 27:1227-1230 |
| Patra, Krushna C; Kato, Yasutaka; Mizukami, Yusuke et al. (2018) Mutant GNAS drives pancreatic tumourigenesis by inducing PKA-mediated SIK suppression and reprogramming lipid metabolism. Nat Cell Biol 20:811-822 |
| Katona, Bryson W; Yurgelun, Matthew B; Garber, Judy E et al. (2018) A counseling framework for moderate-penetrance colorectal cancer susceptibility genes. Genet Med 20:1324-1327 |
| Jeon, Jihyoun; Du, Mengmeng; Schoen, Robert E et al. (2018) Determining Risk of Colorectal Cancer and Starting Age of Screening Based on Lifestyle, Environmental, and Genetic Factors. Gastroenterology 154:2152-2164.e19 |
Showing the most recent 10 out of 590 publications
