Novel Rexinoids Agonists for Cancer and Immunotherapy

Michigan State University Background
KRAS is one of the most common oncogenes that causes normal cells to become cancerous when mutated. Current therapeutics designed to block KRAS function have not shown favorable clinical outcomes and therefore, KRAS has been deemed an “undruggable” target. However, our recent studies have shown that rexinoids are highly effective for treating experimental models of lung and pancreatic cancers driven by KRAS mutations. A currently approved rexinoid, bexarotene, is an agonist for the Retinoid X receptor (RXR) which leads to arrest of cell proliferation. Despite promising results in lung cancer trials, bexarotene was not potent enough as a single agent and generated unwanted toxicity. Therefore, novel RXR agonists with increased efficacy and safety need to be developed. MSU researchers have synthesized novel rexinoid compounds for the purpose of treating various forms of cancer including those with KRAS mutations.
Technology Overview
The researchers have developed novel rexinoids for treatment of the “undruggable” cancers caused by a KRAS mutation. These rexinoids show increased efficacy and safety and novel immunomodulatory activity not observed with the current FDA approved treatment, bexarotene. Additionally, these compounds show a 3-fold increase in binding affinity for the RXR receptor. The researchers have also elucidated a novel mechanism of rexinoids on immune cells, resulting in a decrease in tumor-promoting macrophages, decrease in tumor-promoting myeloid-derived suppressor cells, and an increase in cytotoxic CD8+ T cells. As a result, these new rexinoid compounds enhance efficacy against experimental lung cancer when combined with standard of care chemotherapy or immunotherapy treatments.
Benefits

Improved treatment for “undruggable” cancers with a KRAS mutation
Increased efficacy and safety over bexarotene
Enhanced tumor-suppressing activities
Decrease in macrophages and myeloid-derived suppressor cells
Increase in cytotoxic CD8+ T cells

Applications

Treatment for cancers driven by KRAS mutations (lung, pancreatic and colorectal)
Treatment for resistant HER2+ and triple negative breast cancer (TNBC)
Anti-cancer drugs for veterinary medicine
TEC2018-0088

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