Improving Pancreatic Cancer Therapy Through Understanding and Exploiting SAMHD1 in DNA Repair
Abstract
This proposal will address the Fiscal Year 2016 Peer Reviewed Cancer Research Program Topic Area of pancreatic cancer and Military Relevance Focus Area of military-relevant risk factors associated with pancreatic cancer including genotoxic agents such as ionizing radiation and environmental carcinogens as well as gaps in treatment that may disproportionally affect military Veterans who are at increased risk for pancreatic cancer. Pancreatic cancer is a devastating disease with poor outcomes with current therapies. Therefore, new approaches for treating patients with pancreatic cancer are urgently needed. Military members are at increased risk for pancreatic cancer due to exposure to genotoxic agents such as ionizing radiation (IR) and environmental carcinogens. The primary nonsurgical treatment options for pancreatic cancer involve IR and/or chemotherapy; however, the effectiveness of these treatments is often limited by lack of initial response and/or development of treatment resistance. Identifying a biomarker that will discriminate which patients will respond to IR versus chemotherapy would lead to a paradigm-changing approach that allows the personalized delivery of IR versus chemotherapy treatment. No such biomarker currently exists, likely because the identification of a protein that positively regulates IR response but negatively regulates chemotherapy response or vice versa has remained elusive. We recently identified a novel role for SAMHD1 in the resection of the ends of DNA double-strand breaks (DSBs) to facilitate DNA DSB repair by homologous recombination (HR), a process in which DNA sequences are exchanged between two similar or identical molecules of DNA. SAMHD1 is a protein that has a well-established role in preventing HIV-1 infection by degrading dNTPs or DNA precursors that are required for the virus to replicate. SAMHD1 is also mutated, deleted, or abnormally expressed in pancreatic cancer. Strikingly, we found that SAMHD1 depletion in pancreatic cancer cells causes radiation sensitivity but resistance to two types of chemotherapy that target dNTP metabolism, including HU and 5-FU. We hypothesize that SAMHD1 maintains genome integrity in pancreatic cancer by promoting DNA end resection to facilitate HR. Furthermore, SAMHD1 through dual roles in DNA end resection and dNTP depletion plays a critical role in discriminating resistance to IR and chemotherapies that target dNTP metabolism, which may be exploited for pancreatic cancer therapy. We propose to determine the mechanism by which SAMHD1 function in DNA DSB repair and determine the extent to which SAMHD1 can be exploited as a biomarker for discriminating treatment resistance in pancreatic cancer. This work has significant clinical implication for military members and their beneficiaries with pancreatic cancer, a disease with poor outcomes with current therapies. From the perspective of the genome maintenance field, we expect to determine how SAMHD1 promotes DNA DSB repair by HR and thus provide new insights into how SAMDH1 maintains genome integrity and prevents pancreatic cancer. From the perspective of the cancer therapeutics field, we expect to determine, at least in principle, whether SAMDH1 inhibition can be an effective therapeutic approach with potential to improve clinical outcomes for military members and their beneficiaries. From the perspective of the oncology field, we expect to elucidate SAMHD1 as a novel biomarker for discriminating response of pancreatic cancers to IR and chemotherapies that target nucleotide metabolism so that personalized therapies can be tailored to military members and their beneficiaries. This work will provide preclinical data to inform a randomized clinical trial investigating the use of SAMHD1 as a novel biomarker provide guidance on which patients with pancreatic cancer will benefit from radiation therapy versus chemotherapies that target dNTP metabolism. We hope that within 2 to 3 years, the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710459
Entities
People
- David Yu
Organizations
- Emory University
- United States Army