Exploiting RhoA Mutations in Diffuse Gastric Adenocarcinoma and Targeting Intertwined RhoA and Yap1 Pathways for Therapeutic Advantage
Abstract
Peer Reviewed Cancer Research Program (PRCRP) Topic and Military Relevance: Research proposals on cancer of the stomach are now eligible for funding by the Department of Defense. Stomach cancer is very relevant to our military men and women and their families. Since stomach cancer has been noted to be on the rise, this becomes even more important. There is ample information to support that high stress and Agent Orange can cause cancer of the stomach. In addition, when our men and women travel to areas of high risk for stomach cancer (Japan, Korea, Taiwan, etc.), they become susceptible to local factors (bacterial infection by H. pylori, use of mold-infected pickled foods, or the use of high salt in foods). Dr. Ajani has seen many military men and women with stomach cancer. Even Veterans Affairs Hospitals have conducted studies on stomach cancer and emphasized the need for developing better treatments. Finally, this topic is of such immense importance that Dr. Ajani went to Capitol Hill with a military couple (wife afflicted with stomach cancer) and pleaded to Congress to list stomach cancer as one of the PRCRP Topics. Scientific Objectives and Rationale: The US Government supported a global effort to characterize genomic alterations in various cancers (nearly 300 million dollars were spent). We have learned a lot. Now it is time to use this information and help our patients. This effort called TCGA (The Cancer Genomic Atlas) uncovered that the gene RhoA is mutated in some patients with stomach cancer. It is likely that this mutation is helping some stomach cancers grow. We want to take advantage of this knowledge and study it in detail. We have considerable experience with another gene in stomach cancer called Yap1. We feel certain that RhoA and Yap1 cooperate to allow cancer growth. We want to disrupt the proteins produced by these two stomach cancer genes. Ultimate Applicability of the Research: What we are proposing is unique. Stomach cancer patients and their families are desperate and we let them down all the time. If we complete this research, there is a chance that an entirely novel treatment can be made available to stomach cancer patients. We propose to stop the RhoA and Yap1 proteins in patients who have an RhoA mutation and an excessive amount of Yap1 protein. We are also proposing to establish genetically engineered mouse model relevant to these two genes. Dr. Johnson in our group does this routinely, and we do not foresee problems in developing a novel genetic mouse model. The drugs to inhibit RhoA and Yap1 protein are already in the clinic. We foresee that a successful project may allow us to propose the trial in patients in the next 3-4 years. Not only we will advance research in stomach cancer, the novel technical knowledge will thrust the fight against other cancers forward. A much larger group is like to benefit. Relevance to Active Duty Service Members/Families and Other Military Beneficiaries: We have already identified stomach cancer as a health problem for Service members. This is related to many factors: risks, stress, chemical exposures, and change in lifestyle. Our unique research will uncover vulnerabilities in stomach cancer that can be exploited. If our results are positive, we will open up the door to help all susceptible Service members (on and off duty) and their families and other employees who serve our military members.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610234
Entities
People
- Jaffer Ajani
Organizations
- United States Army
- University of Texas at Austin