Unbiased Screening for Identification of Effective Combination Therapies Targeting Oncogenic Pathways in Colorectal Cancer
Abstract
Colorectal cancer (CRC) is the fourth most common cancer in the US military population and is the second leading cause of cancer-related death in the United States leading to the death of nearly 50,000 patients per year. Most of the deaths are due to metastatic colorectal cancer (mCRC) where surgical removal of the tumors that have spread to distant organs is rarely possible. Patients with mCRC are now treated with combinations of chemotherapy sometimes in combination with a "targeted" therapy (therapy targeting a biological process involved in tumor growth). Despite the study of many promising agents in clinical trials, no significant improvements in actual therapy have been made in treating patients with mCRC in the past decade. Most of the new clinical trials are not innovative and attempt to test various combinations of chemotherapy with one or more therapies that targeted therapies. Such studies have produced disappointing results and, in certain instances, have actually shortened patients lives. This has prompted a strong need to identify more novel approaches in identifying therapies that will improve treatment of patients with mCRC. With improved understanding of the genetic alterations that lead to cancer growth, scientists have identified specific alterations (mutations) in important genes in CRC. These mutations have also been indicated to drive tumor growth and hence named "driver mutations." These driver mutations serve as attractive targets for therapy. However, clinical trials with single drugs targeting these mutations in CRC have failed to improve patient survival. We hypothesize that combination therapies that include one drug targeting a driver mutation and a second drug identified by completely unbiased screening that can be done on a large number of agents simultaneously will be more effective at identifying effective combination therapies that, in turn, will provide maximum benefit for our patients. We plan to perform screening studies with compounds that are either Food and Drug Administration-approved or in clinical trials so that the combination therapies identified in our studies can be quickly studied in clinical trials. We expect that findings from our novel, unbiased approach will quickly help formulate the foundation of clinical trials that are likely to succeed in providing significant improvements in increasing survival in patients with mCRC. The contributions of these studies will be very significant. The short-term outcome of this proposal will be to perform preclinical studies and identify novel and more effective combination therapies targeting "driver mutations" in CRC cells using unbiased drug library screens. The long-term outcome of this work is to utilize our preclinical data to provide a 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 methods to improve treatment of patients with mCRC, our studies will benefit our military personnel who are subject to stressors (inflammation, psychological stress, etc.) that can lead to CRC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510126
Entities
People
- Lee M. Ellis
Organizations
- United States Army
- University of Texas at Austin