Inhibitors of Gas6-Axl Signaling Pathway as First of Kind Cancer Therapeutics

Gas6 activates TAM receptor (Axl)inducing signaling cascade to promote tumor cell proliferation, migration and survival.

Invention Summary:

TAM receptors (Tyro-3, Axl, and Mer) belong to a family of receptor tyrosine kinases (RTKs) that play essential roles in homeostasis and inflammation. Axl is overexpressed in many human cancers and is clinically associated with poor survival outcomes and drug resistance. Axl is activated by Growth Arrest Specific Gene 6 (Gas6), which is also overexpressed in many cancers.

Rutgers researchers and collaborators utilized a computational method to identify several tyrosine kinase inhibitors (TKIs) that compete with Gas6 for binding to the TAM receptor to elicit anti-cancer effects. The Gas6-induced TAM activation signaling pathway is associated with tumor proliferation, migration, and immune cell evasion. Several small-molecule tyrosine kinase inhibitors (TKIs) are in preclinical and clinical trials. These conventional kinase inhibitors bind to intracellular ligands and induce off-target effects. This invention acts endogenously, exhibiting selective effects with fewer side effects, while suppressing tumor growth. In vitro and in vivo tests demonstrated that some of them had anti-cancer activities without discernible toxicity to normal cells. These drug candidates could represent the first of their kind in cancer therapeutics.

Market Applications:

• Aggressive and drug-resistant tumors such as small-cell lung carcinoma and breast cancers.
• Development of first-in-class drugs with improved safety and efficacy.
• Potential for expansion into other diseases involving TAM receptor dysregulation.

Advantages:

• Greater selectivity, specificity, and efficiency by targeting the extracellular domain
• Improved safety profile with fewer side effects
• Potential to overcome drug resistance seen in current TAM-targeting therapies

Publications:

• Kimani SG, Kumar S, Bansal N, Singh K, Kholodovych V, Comollo T, Peng Y, Kotenko SV, Sarafianos SG, Bertino JR, Welsh WJ, Birge RB. Small molecule inhibitors block Gas6-inducible TAM activation and tumorigenicity. Sci Rep. 2017 Mar 8;7:43908. doi: 10.1038/srep43908. PMID: 28272423; PMCID: PMC5341070.

Intellectual Property & Development Status:

Patent issued US 10,851,096 and European Patent Convention 3471729 (France, UK, and Germany). Available for licensing and/or research collaboration. For any business development and other collaborative partnerships, contact marketingbd@research.rutgers.edu.