Immune-Suppression and Tumor-Stromal Interaction Mediated by Galectin-3 in Gastric Cancer - Implications of Novel Therapeutic Strategies
Abstract
Peer Reviewed Cancer Research Program (PRCRP) Topic and Military Relevance: Gastric adenocarcinoma (GAC) is a global health problem, and military personnel are affected by it. 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. Dr. Ajani has seen many military men and women with stomach cancer. Even Department of Veterans Affairs (VA) Hospitals have conducted studies on stomach cancer and emphasized the need for developing better treatments. Finally, this topic of such immense importance that Dr. Ajani went to Capitol Hill with a military couple (wife afflicted with stomach cancer) and pleaded with Congress to list stomach cancer as one of the PRCRP Topics. Scientific Objectives and Rationale: Immune system is often suppressed where a tumor grows in the body, but early results show that immune system can be stimulated to attack a patient?s GAC. Unfortunately, every patient does not realize this benefit. We need to work hard to find the role of galactin-3 in suppressing the immune system. We are proposing a comprehensive approach to study galactin-3 that can be found in the tumor bed (also called stroma), tumor cells, and in small vesicles released by GAC and other cells. We believe (hypothesis) that galactin-3 is a critical molecule that suppresses the immune system of the host and allows the cancer to prosper. We would like to study various types of immune and not immune cells in the tumor bed. We will manipulate the environment by assessing the levels of galactin-3 by observing the effects of interrupting galactin-3 by a drug called TD139 and combining it with other drugs (like anti-PD-L1, anti-CD47, or anti- CSF1R). We will collaborate with Dr. Liu (University of California at Davis) who has sophisticated genetically engineered mice that do not have gene for galactin-3. To understand the role of galactin-3, these mice will be enormously important for our experiments. We have three elaborate goals to answer the questions being asked by our group. We are very familiar with the technology proposed in our application. We have some experience with galactin-3 that predominately lives inside the cell. In this proposal, we will study how galactin-3 activates different cells of the tumor bed to protect tumor cells from being killed by our immune system. We will be able to assess the galactin-3 (either its excess or lack of it) on tumor survival and reaction of other tumor bed cell groups. Ultimate Applicability of the Research: What we are proposing is unique. Patients and families with stomach cancer 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 deplete galectin-3 (gal3-/-) or addition of galectin-3 inhibitor will boost our immune system to kill tumor cells especially in combination with using anti-PD-L1 antibody (another anti-immune suppression therapy) and inhibitors of other immune suppressed molecules -- CD47 or CSF1R. In addition, it may be that galactin-3 will serve as an important biomarker that will be linked to GAC and ultimately to selective personnel and their families. How This Is Relevant to Active Duty Service Members/Families and Other Military Beneficiaries: GAC is highly relevant to our troops and their families. Patients with advanced GAC have very poor survival (<10 months). Troops have been engaged in endemic areas of GAC (Japan/Korea/Taiwan) and are susceptible to high-risk, region-specific factors (H. pylori, pickled food with carcinogens, and high salt diet). In addition, the reported increase in the risk of GAC among younger individuals imposes another health risk. Dr. Ajani, a co-investigator on this project, has treated several Service men/women with gastric cancer. He also went to Capitol Hill to reques
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710293
Entities
People
- Shumei Song
Organizations
- United States Army
- University of Texas at Austin