Dissecting SOX9-Mediated Cancer Stemness and Immunosuppression for Novel Strategies in Advanced Gastric Adenocarcinoma
Abstract
Gastric adenocarcinoma (GAC) is a major health burden in the United States (U.S.) and globally, where there are more than 1 million new cases/year and in U.S., 26,000 cases are expected. GAC is a leading cause of death in 10 countries. GAC is also relevant to our military personnel, Veterans, and their families. Even today, most patients are diagnosed in advanced stage and have a poor overall survival of less than 12 months. Therapies are quite limited in the clinic, and often we are guessing. Thus, much more research is needed before we can improve the outcomes of patients with GAC. We want to identify new and effective drugs for GAC patients in whom the cancer has already spread (stage IV) around the intestines. When this happens, patients have many debilitating symptoms and require high level of constant care. Current treatments are not very effective. The majority of GAC patients are diagnosed late and, unfortunately, do not survive very long. We need to discover better drugs. We have developed a good model to test new drugs, and we are using patient-derived tissues. To address this unmet clinical challenge, we have leveraged our clinical resources. We are proposing a novel target, SOX9, a stem cell gene that is used by tumor cells or cancer stem cells for their growth and spread advantage. We noticed in our metastatic patients’ tissues that SOX9 is high, and high levels of SOX9 are associated with poor survival. Interestingly, if we remove SOX9 in tumor cells, the tumor cells shrink and stop growing. Even more interestingly, we noticed high SOX9 in tumor cells can block T cell attacking of the tumor cells and production of less weapon (IFN-gamma, Granzyme B and perforin) to kill tumor cells, while removal of SOX9 in tumor cells leads to T cells getting energized. We propose that PC with high SOX9 helps cancer cells to become stage IV and have aggressive behavior by activation of LIF factor to prevent immune cells from attacking tumor cells. When we inhibit LIF in SOX9 high tumors, we can eliminate tumor cells as well as reactivate T cells immune responses. To test our hypothesis, the following three goals (aims) are proposed. Aim 1: Determine the role of SOX9 in GAC stemness and metastases using novel stem cell cloning technology and patient-derived orthotopic (PDO) metastatic model and genetic mouse model. Aim 2: Elucidate SOX9-mediated immune suppression and metastases by activation of LIF/LIFR axis. Aim 3: Preclinical evaluation of inhibition LIF alone in PDX model and other immune checkpoint blockage (PDL-1i) in syngeneic models as well as our aggressive GAC GEM KPCS model. We will also optimize combination treatment strategies with conventional therapy and other immune checkpoint therapy PD1i, which used in clinics. We believe that results from this study will reveal the role of SOX9-mediated PC and immunosuppression by activating LIF, an important factor to suppress T cell responses, establish preclinical platforms, and facilitate development of novel drug strategies for GAC patients with PC. Given the importance of the SOX9/LIF axis we have uncovered, we predict that completion of these studies will provide strong rationale for novel clinical trials which benefit GAC patients with PC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210381
Entities
People
- Shumei Song
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army