Mechanism-Based Combination Targeted Therapy for Colorectal Cancer
Abstract
Targeted therapy, or precision therapy, has become a standard of care for many types of cancer. This therapy uses drugs to specifically block the function of cancer-causing genes that drive cancer cell growth. Because targeted therapy blocks cancer-specific processes, it has low toxicity compared to traditional chemotherapy. While targeted therapy works well for those cancers that are addicted to a dominant cancer driver gene, most cancers are driven by multiple cancer driver genes. Such multi-driver cancers require a combination of drugs, collectively blocking all drivers, for effective treatment. Fiscal Year 2020 (FY20) Peer Reviewed Cancer Research Program (PRCRP) topic area to be addressed: Colorectal cancer. Colorectal cancer is the third leading cause of cancer-related deaths in the United States and the world, but it still does not have broadly effective targeted therapy. One of the reasons for the lack of effective targeted therapy for colorectal cancer is that its development and progression are driven by multiple genes. Although some combination targeted therapies have been developed, the response rates are low, and more broadly effective combination therapies are still urgently needed. Currently, identification of drug combinations relies on empirical screening or educated guesses. The proposed research aims to develop a rational strategy of formulating mechanism-based combination targeted therapy. Preliminary studies developed a new mathematical model for analyzing how multi-driver cancer cells respond to targeted therapy, which provides a platform for identifying multiple drug targets in multi-driver cancer cells and formulating effective drug combinations for colorectal cancer. Application of this approach revealed a prevalent reliance on a common set of drivers in most CRC cells, and identified common drug combinations that are extremely effective against a majority of CRC cells. These studies established a rational strategy for formulating mechanism-based drug combinations for multi-driver cancers in vitro. This proposal aims to validate this strategy in the full CRC molecular landscape and in patient-derived animal CRC models. The FY20 PRCRP Military Heath Focus Area this proposal addresses is: Gaps in cancer prevention, early detection/diagnosis, prognosis, treatment, and/or survivorship that may affect the general population but have a particularly profound impact on the health and well-being of military Service members, Veterans, and their beneficiaries. The research has the potential of providing important insights into what sustains the progression of colorectal cancer cells and finding an effective mechanism-based targeted therapy for treating colorectal cancer. Thus, this research has direct applications to cancer treatment. As the third leading cause of cancer-related deaths, colorectal cancer places a major heath, life, and economic burden on Service Members, Veterans, and their families. Thus, finding effective treatments for colorectal cancer will greatly benefit the military patients suffering colorectal cancer and help improve the mission readiness of the US military.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110598
Entities
People
- Gongqin Sun
Organizations
- United States Army
- University of Rhode Island