Development of first-in-class antagonists of the retinoid pathway as novel oral immunotherapies for solid cancers

Project Summary: The majority of cancer deaths are caused by dissemination and growth of secondary tumors throughout the body. While the 5-year survival rate for localized cancers has dramatically improved over the last four decades of drug development, the survival rates for cancer patients with advanced or metastatic disease remains abysmal, with median survival of Stage 4 patients at 10 months following diagnosis. Patients diagnosed with advanced or metastatic cancers are furthermore considered terminal as metastatic lesions are resistant to current therapeutic options. New therapeutic agents that can effectively treat and enforce regression of advanced cancers or established metastases are urgently needed in the therapeutic repertoire, yet only immune checkpoint blockade therapies have shown the ability to prolong survival in a small subset of patients with Stage 4 cancer. Therefore, immunotherapies with novel mechanisms of action and complementarity to current therapies are urgently needed to increase the percentage of responding patients and improve cancer survival metrics in the United States. Our academic collaborators as well as other leading academic laboratories have identified an immunosuppressive signaling pathway driven by two complementary enzymes that is critical to the progression of solid tumors by generating an immunosuppressive tumor microenvironment. Both our discovery work and recently published studies demonstrate this pathway is a critical node in the progression of multiple cancer types such as sarcoma, melanoma and breast cancer, yet prior commercial and academic attempts to drug this pathway have failed due to lack of potency, specificity and/or poor pharmacological properties. We are the first group to have developed lead compounds against this pathway that show exceptional potency and specificity while avoiding the pharmacologic liabilities of other drug development programs. Importantly, our therapies show promise in treating advanced and metastatic cancers and are characterized by low nanomolar potency (lt50 nM, a 100-fold improvement over published molecules), no off-target activity, high metabolic stability, excellent oral pharmacokinetic properties and promising in vivo toxicology. Here we propose to nominate a development candidate through pharmacodynamic assays, dose-range finding studies and immunocompetent cancer models. The results of this research proposal will advance a first-in-class therapy toward clinical testing with the aim of curing patients who were once diagnosed as incurable. Specifically, the efficacy and preclinical data obtained from this application will support Phase 2 SBIR studies leading to an IND application.