Identification and Validation of Novel Combination Therapies for KRAS-Mutated Colorectal Cancer Using Unbiased and Innovative Screening Strategies
Abstract
The proposed study addresses the Fiscal Year 2018 (FY18) Peer Reviewed Cancer Research Program (PRCRP) Military Relevance Focus Area of Colorectal Cancer (CRC) and its potential benefits to military personnel and their families are significant. CRC is the responsible for the second largest number of cancer related deaths in the United States and is expected to result in about 50,000 deaths this year. It is also one of the top four cancers that effect the military personnel and Veterans in this country. Most of the deaths are due to metastatic colorectal cancer (mCRC), in which surgical removal of the tumors that have spread to distant organs is rarely possible. Presently, patients with mCRC are treated with combinations of chemotherapies with or without targeted therapies (therapy targeting a biological process involved in tumor growth). However, all patients become resistant to therapy, resulting in poor survival. Recently, immunotherapies have demonstrated activity in patients with mCRC, but these therapies are effective in less than 5% of patients with metastases who have specific genetic defects in the ability of cells to repair mistakes in their DNA that occur during cell division. Effective therapies for more than 95% of patients with mCRC are desperately needed. With an improved understanding of the genetic alterations that lead to cancer growth, scientists have identified specific alterations (mutations) in important genes in mCRC that drive the growth of tumor cells and control sensitivity or resistance to therapy. One such driver is K-RAS, which is mutated in about 50% of all mCRC. Targeting K-RAS has led to development of drugs that show promise in other cancer types, but have failed as single agents in patients with mCRC. We hypothesized that finding the right combinations of drugs that target driver mutations along with other important cellular pathways, will increase tumor cell death and be more effective in the treatment of patients with mCRC. With our goal to quickly validate the findings from our laboratory into the clinic, we have screened two large sets of compounds that are either approved by the Food and Drug Administration or are in clinical trials and successfully identified specific combinations that can significantly enhance cell death in CRC cells with K-RAS mutations. To advance these combination therapies to clinical trials, they must be validated in animal models of CRC. In this proposal, we plan to perform preclinical studies in mice models for efficacy of these combination therapies and perform molecular analyses to determine why such combinations are effective. In a different novel approach to identify other novel effective combination therapies, we have identified a set of compounds that can kill or inhibit CRC cell growth. Using these limited number of active compounds, we plan to perform innovative screening studies to identify and validate yet unknown combination therapies effective in preclinical models of mCRC. We hope that our studies will be the foundation of clinical trials that can lead to therapies to improve survival of a large proportion of patients (~50%) with mCRC. The contributions of these studies will be very significant. As the outcome of the proposed work, we expect that our preclinical studies will provide a solid foundation for innovative and efficient clinical trials that, in turn, will enhance survival of patients with mCRC, including our military personnel, Veterans, and their families. With CRC being the fourth most common cancer in military personnel, and the relative lack of innovative approaches to improve the treatment of patients with mCRC, our studies will benefit our military personnel who are subject to stressors (inflammation, etc.) that can lead to CRC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910620
Entities
People
- Rajat Bhattacharya
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army