Advanced colorectal carcinoma is currently incurable, and new therapies are urgently needed. Ephrin (Eph) receptors are a clinically relevant class of receptor tyrosine kinases. Related signaling pathways are associated with oncogenesis of a number of cancers. NCI investigators found that phosphotyrosine-dependent Eph receptor signaling sustains colorectal carcinoma cell survival, thereby uncovering a survival pathway active in colorectal carcinoma cells. Furthermore, colorectal cancers express the EphrinB2 ligand and its Eph receptors at significantly higher levels than numerous other cancer types. Colorectal cancer patients with the highest levels of EphrinB2 expression in their tumor have a lower probability of survival than those with the lowest levels.
The NCI investigators found that a small-molecule inhibitor of the Eph kinase, NVP-BHG712 and its regioisomer NVP-Iso, reduce human colorectal cancer cell growth in vitro and tumor growth in mice. Proof-of-concept data demonstrate inhibition of the Eph tyrosine kinase inhibits the growth of human colorectal carcinomas. Eph signaling sustains colorectal carcinoma cell survival and growth and that inhibition of the phosphotyrosine‐dependent Eph signaling is effective at blocking this prosurvival function. Several derivatives of these prototype compounds have been synthesized and tested for inhibition of the Eph tyrosine kinase activity. Two of these new derivatives have promising biochemical and functional profiles. These small molecule inhibitors have the potential to be developed as a therapeutic for colorectal cancers, other types of Eph-growth dependent tumors, and diseases where the Eph kinase plays a pathogenic role.
- Therapeutics for colorectal cancer
- Therapeutics for other Eph growth-dependent cancers, including breast, lung, prostate, and brain
- Differs in targeting selectivity from many other tyrosine kinase inhibitors
- Distinct mechanism of action from Regorafenib, the only existing receptor tyrosine inhibitor approved to treat metastatic colorectal cancer; Regorafenib is a multi-targeted tyrosine kinase inhibitor developed to inhibit VEGF-dependent tumor angiogenesis
- Promising combination therapy when used with other tyrosine kinase inhibitors and antibodies – such as Cetuximab (approved for metastatic colorectal cancer)
- Overcome resistance to EGFR or BRAF treatment in various tumor types; attributed to EphA2 kinase activity
Michael DiPrima (NCI), Giovanna Tosato (NCI)
Diprima M, et al. Identification of Eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma. [(PMID 31545551)]
- PCT: PCT Application Number PCT/US2020/050439 , Filed 11 Sep 2020