Modulate Innate Immune Responses to Customize Therapy in ARID1A-Deficient Gastric Adenocarcinoma
Abstract
Fiscal Year 2021 (FY21) Peer Reviewed Cancer Research Program (PRCRP) Focus: Stomach Cancer Stomach cancer is a common illness in the United States (U.S.) with more than 26,000 new cases per year. It is even a much larger problem in the world with over 1.2 million new cases per year, and it is the third most common cause of death from cancer globally. Stomach cancer is the top cause of cancer-related deaths in 10 countries. Since we do not have methods in place to detect stomach cancer early, most patients are diagnosed when it is far advanced. Stage IV stomach cancer is deadly. Treatments have limited effect. Only less than 5 out of 100 patients survive with stage IV beyond 5 years. Once a stage IV stomach cancer patient has exhausted first treatment (first regimen), their outlook is very poor, and they are miserable, with a lot of symptom and short survival. To clearly understand what we are proposing in this application, we would like to explain how normal and cancer cells are at the very basic levels. Our bodies are nicely regulated. If the blood glucose goes up, insulin goes up to normalize the blood glucose level. If we make too much thyroid hormone, another chemical (TSH) will suppress it. Normal cells also have this type of balance. But in cancer cells, some of these regulations are lost (damage to the genes). One important group of genes is called Tumor Suppressor Genes (TSGs). TSGs regulate another (opposite) type of genes called oncogenes. Oncogenes are the ones that help cancer multiply and migrate. Oncogenes also help the cancer cells evade the immune system. Gastric cancers often have loss of a TSG called ARID1A. Loss of ARID1A will allow several oncogenes to increase their activity (mTOR is one example) but may lead to other changes. One important change when ARID1A is lost is that cancer cells cannot properly repair its DNA. Unrepaired DNA accumulates. This can be dangerous for cancer cells, as the immune system is alerted when there are a lot of pieces of unrepaired DNA. In our proposal, we want to take advantage of these changes in the stomach cancer cells to advance our understanding on how to develop strategies into treatments for patients. Our group has made many of the discoveries described in our grant. This means we are very familiar with the results of ARID1A loss and have published extensively (but piecemeal) to show how we can win in different circumstances. In this proposal, we now suggest bringing all our discoveries together (convergence) in a rational manner to amplify the effects against cancer. We are certain that the combined strategy will produce a much greater advantage for gastric cancer patients. We now want to converge three approaches and take this to the clinic. We propose three different steps to systematically reach a point when it will likely become clear how to take the new knowledge into the clinic. In that sense, we have already done a lot of basic work, and now we want to rapidly move into the clinic. This should be considered a strength of our proposal. Dr. Peng is an expert on ARID1A loss, Dr. Ajani has considerable clinical and laboratory expertise in stomach cancer, and they have worked together for several years. We have published our discoveries in prestigious journals. We are familiar with the technology we are proposing. We believe our proposal is very novel and high impact. We believe that Dr. Ajani will be able to launch a clinical trial for stomach cancer patients with ARID1A loss. This has never been done and clearly will be a departure from what we do in the clinic today. Types of Patients: Advanced stomach cancer patients where ARID1A is lost (about 30% of all stage IV patients). Innovation: This is a highly innovative proposal. It is based on our unique discoveries and we hope to combine our discoveries into a single and safe clinical strategy. PRCRP Focus: We are focusing on Gastric Cancer for FY21 P
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210559
Entities
People
- Jaffer Ajani
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army