Combinatorial therapies to improve immune-mediated approaches for osteosarcoma
Scientific objective and rationale
Overall survival rates for Osteosarcoma (OS) remain about 65-75% and are significantly worse for patients with advanced or relapsed disease, often with long-term outcomes of less than 30%. Therefore, alternative therapeutic approaches are needed. Using the patient’s immune system to help target and eliminate the tumor has been an active area of research for many cancers. Prior studies have reported the significance of a tumor microenvironment that inhibits the OS patient’s immune system from targeting the tumor. Unfortunately, there has been minimal success using immune alteration therapies for sarcomas. To effectively evaluate candidate immune altering approaches and compounds, it is essential to test on relevant models. Using novel genetically altered mice that our laboratory has developed to mimic osteosarcoma tumor initiation and development, we have been actively studying the biology of the tumor cells and non-tumor cells, including immune cells. Our mouse models also provide valuable tumor cell resources that allow us to perform studies evaluating the effects of immunotherapy, or small molecules that alter the immune system. The overall objectives are focused on (1) assessing the effects of combination immune altering drugs and targeted kinase inhibitors on osteosarcoma development and metastatic progression and; (2) to perform comprehensive molecular characterization of the effects the combination therapies have on the tumor environment. Specifically, we will test several small molecules targeting key tumor-promoting pathways in OS, including the kinase inhibitors Cabozantinib and the beta-catenin inhibitor Tegavivint. These drugs have recently shown anti-tumor activity for osteosarcoma as single agents. Besides targeting the tumor cells, these inhibitors alter the behavior of the immune cells in other cancers. Our studies will provide essential molecular insights and pre-clinical assessment of rational combination therapy that can lead to clinical trials.
Impact
While chemotherapy has been the standard of care, and the evaluation of targeted therapies, such as multi-tyrosine kinase inhibitors, have been used to treat pediatric sarcomas, these therapies have primarily focused on the primary tumor cell biology. More recently, there has been a tremendous focus on using the patient’s immune system to help target the tumor. Investigating the applications of immunotherapy to treat OS is an emerging field, as we are learning more about the OS tumor microenvironment. One class of small molecules includes immune checkpoint inhibitors (ICI). While ICIs have shown promise in some adult cancers, previous clinical trials using ICI as monotherapy have proven ineffective in OS. To effectively investigate the potential applications of immunotherapy to treat OS, it is essential to evaluate candidate immunotherapeutic approaches and compounds, including checkpoint inhibitors, on relevant, immune competent models. Our laboratory has developed and extensively characterized genetically engineered mouse models of OS, which mimic the molecular pathogenesis, development, and progression of the disease. Using our tremendous expertise and familiarity with our high-risk phenotypic and molecular syngeneic models, we will perform highly efficient combinatorial pre-clinical trials, so promising combinations are prioritized for subsequent trial consideration. In addition, our proposed spatial molecular studies will undoubtedly reveal proteo-transcriptomic insights into tumor evolution in response to single-agent and combinatorial therapy. Our studies can be transformative and provide rationale treatment regimens implementing immunotherapeutic approaches for high-risk OS patients, thus addressing an unmet need for a substantial patient cohort in dire demand for effective alternative therapies.
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