Precision Approaches to Early-Onset Colorectal Cancer Therapy Through Germline Variation
Abstract
This project focuses on colorectal cancer, a Fiscal Year 2018 (FY18) Peer Reviewed Cancer Research Program Congressionally Directed Topic Area, and addresses several of the FY18 Military Relevance Focus Areas, specifically gaps in colorectal cancer prevention and treatment strategies. Objective and Rationale: Colorectal cancer deaths remain the second leading cause of cancer deaths in the United States. Despite screening programs, cases of early-onset colorectal cancer, defined as those diagnosed before the age of 50, are sharply rising. These young individuals often present at advanced stages. Our preliminary data suggest that individuals with early-onset colorectal cancers, and without strong family histories, frequently have mutations in DNA repair genes already implicated in other cancers such as breast cancer and leukemia. While these mutations in DNA repair genes predispose someone to develop early-onset colorectal cancer, they simultaneously create new vulnerabilities to specific chemotherapies not commonly used for this cancer type. Thus, the mutations in DNA repair genes present in a person since birth may suggest that specific, precise chemotherapies may work better in treating their colon cancer than the regimens currently utilized. This treatment strategy is a stark departure from the present where we focus exclusively on the DNA changes found in a persons tumor. The first goal of this proposal is to demonstrate through novel 3-D model systems of patient-derived normal colon and cancer tissue, mutations present since birth may be equal if not more important in drug selection than the mutations present in cancer. The second goal is to correlate signatures found in tumor mutations with inherited mutations. Research Applicability: These data will also provide proof-of-principle for routine precision cancer therapeutics based on patients inherited genetic profile in addition to the molecular features of their tumor. In a more immediate fashion, these results could prompt clinical trials of Food and Drug Administration (FDA)-approved chemotherapeutics already used for different cancer types for cases of early-onset colorectal cancer with these specific mutations. Second, results can be used to further identify individuals who may benefit from genetic testing from the signatures of the mutations present in the tumor. Military Relevance: The rising incidence of colorectal cancer among the young will pose significant challenges to Department of Defense Healthcare Facilities, in addition to the Veterans Administration. Since military personnel are exposed to colorectal carcinogens such as industrial solvents and radiation, knowledge of mutations in DNA repair genes and the changes they make in tumors may permit precision medicine and prevention strategies for those individuals who are more vulnerable to their cancer-causing effects.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910784
Entities
People
- Manish Gala
Organizations
- Massachusetts General Hospital
- United States Army