Novel Rexinoid Agonists for Kras-mediated cancer and immunotherapy
KRAS is one of the most common oncogenes that, when mutated, causes normal cells to become cancerous. Current therapeutics designed to block KRAS function have not shown favorable clinical outcomes and therefore, KRAS has been deemed an “undruggable” target. However, our studies demonstrate that novel, appropriately substituted rexinoids are highly effective in clinically relevant 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 failed to meet the desired clinical efficacy endpoints as a single agent and unwanted toxicity was observed. Therefore, novel RXR agonists with increased efficacy and safety are desirable. MSU researchers have identified novel rexinoids for the purpose of treating multiple cancers including those with KRAS mutations and provide favorable outcomes in standard-of-care combination studies with both chemotherapies and PD-1 or PD-L1 immunotherapies.
Description of Technology:
Our 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. Our 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 analogs enhance efficacy in relevant lung and pancreatic cancer models when combined with standard of care chemotherapy or immunotherapy targeting PD-1 and PD-L1.
- 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
- Treatment for cancers driven by KRAS mutations (lung, pancreatic and colorectal)
- Treatment for HER2+ and triple negative breast cancer (TNBC) with activated Ras signaling
- Enhanced outcomes when combined with standard-of-care therapies, including chemotherapy and PD-1 orPD-L1 immunotherapies.
- Anti-cancer drugs for veterinary medicine
Licensing Rights Available:
Full licensing rights available
Karen T. Liby, Edmund L. Ellsworth, Ana Sofia Mendes Leal, Bilal Aleiwi
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Michigan State University