Despite recent advancements, metastatic pancreatic cancer remains a lethal disease with an average survival of less than one year. New targeted treatments are desperately needed. Identifying and expanding patient subgroups that would benefit most from promising targeted agents will immediately impact patient outcomes. The primary impact of our proposal relates to the clinical implementation of PARP inhibitors, harnessing a proven synthetic lethal therapeutic strategy personalized for a subset of pancreatic cancer patients. Recent whole genome sequencing of 100 pancreatic cancers highlighted the opportunity to use PARP inhibitor therapy targeted for tumors with a `DNA repair-BRCA-signature' subtype. Our work will expand three fronts of investigation and innovation in an effort to optimize the most promising drug class for pancreatic ductal adenocarcinoma patients.
Aim 1 will expand our recent discovery that a post- transcriptional mechanism driven by the mRNA stability factor HuR, provides a resistance mechanism for pancreatic cancer cells exposed to PARP inhibitors. In this aim, we will extend our pre-clinical mouse modeling to establish HuR as a facilitator of PARP inhibitor resistance and establish that inhibiting HuR may sensitize all pancreatic tumors, regardless of DNA repair status, to PARP inhibitors.
Aim 2 will further define, using cutting edge molecular and cell-based techniques and assays, a PARP inhibitor mechanism of action which is contingent upon a novel HuR-regulated target [i.e., (Poly(ADP-ribose) glycohydrolase (PARG)].
Aim 3 will leverage our molecular understanding of HuR biology and the identification of two small molecule inhibitors of HuR to develop novel and translatable strategies to enhance PARP inhibitor efficacy using a patient derived (i.e., organoid technology), live biobank from an ongoing PARP inhibitor trial conducted by investigators from the present proposal. The translational significance of our work relates to our efforts to improve upon a promising, personalized approach to pancreatic cancer through increased understanding of a recently discovered PARP inhibitor resistance mechanism. Our ultimate aim is to optimize a best-in-class treatment strategy presently limited to tumors harboring DNA repair deficiencies, so that this therapeutic strategy may be extended to include all pancreatic cancers, regardless of the DNA-repair status (i.e., BRCA2 mutant and wild type).
PARP inhibitors have generated much excitement in the pancreatic cancer research community, particularly in pre-clinical studies and in early phase clinical trials for patients who harbor BRCA2 mutations. Our proposed studies will advance our understanding of currently available PARP inhibitors by investigating a novel and potent drug resistance mechanism. Ultimately, our goal is to develop a strategy that will optimize the use of PARP inhibitor-based therapies for all pancreatic cancer patients.
|Maranto, Cristina; Udhane, Vindhya; Hoang, David T et al. (2018) STAT5A/B Blockade Sensitizes Prostate Cancer to Radiation through Inhibition of RAD51 and DNA Repair. Clin Cancer Res 24:1917-1931|
|Heeke, Arielle L; Pishvaian, Michael J; Lynce, Filipa et al. (2018) Prevalence of Homologous Recombination-Related Gene Mutations Across Multiple Cancer Types. JCO Precis Oncol 2018:|
|Peng, Weidan; Furuuchi, Narumi; Aslanukova, Ludmila et al. (2018) Elevated HuR in Pancreas Promotes a Pancreatitis-Like Inflammatory Microenvironment That Facilitates Tumor Development. Mol Cell Biol 38:|
|Tiriac, Hervé; Belleau, Pascal; Engle, Dannielle D et al. (2018) Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer. Cancer Discov 8:1112-1129|
|Pishvaian, Michael J; Slack, Rebecca S; Jiang, Wei et al. (2018) A phase 2 study of the PARP inhibitor veliparib plus temozolomide in patients with heavily pretreated metastatic colorectal cancer. Cancer 124:2337-2346|
|Brody, Jonathan R; Dixon, Dan A (2018) Complex HuR function in pancreatic cancer cells. Wiley Interdiscip Rev RNA 9:e1469|
|Lal, Shruti; Cheung, Edwin C; Zarei, Mahsa et al. (2017) CRISPR Knockout of the HuR Gene Causes a Xenograft Lethal Phenotype. Mol Cancer Res 15:696-707|
|Chand, Saswati N; Zarei, Mahsa; Schiewer, Matthew J et al. (2017) Posttranscriptional Regulation of PARG mRNA by HuR Facilitates DNA Repair and Resistance to PARP Inhibitors. Cancer Res 77:5011-5025|
|Zarei, Mahsa; Lal, Shruti; Parker, Seth J et al. (2017) Posttranscriptional Upregulation of IDH1 by HuR Establishes a Powerful Survival Phenotype in Pancreatic Cancer Cells. Cancer Res 77:4460-4471|