Abstract 1936: The central role of NFAT signalling in the mechanism of action of the TRPV6 oncochannel inhibitor and clinical candidate SOR-C13

SOR-C13, a 13-mer peptide derived from soricidin, the paralytic peptide in saliva of the Northern Short-tailed shrew, has completed an open-label, all comers Phase I Clinical Trial for the treatment of epithelially-derived cancers. SOR-C13 is a first-in-class drug candidate for the treatment of solid tumors. SOR-C13 specifically targets and inhibits the TRPV6 calcium channel - a recognized oncochannel whose over-expression in a number of epithelial cancers (e.g. breast, ovarian, prostate) is associated with poor prognosis. An increase in TRPV6 facilitates calcium influx into the cell, which activates the calcium binding protein calmodulin. This complex in turn activates calcineurin that de-phosphorylates and activates Nuclear Factor of Activated T-cells (NFAT), a gene transcription factor involved in multiple oncogenic processes. To demonstrate the role of NFAT activation in the mechanism of action (MOA) of SOR-C13, breast cancer cells (T-47D) were transfected with a NFAT dual reporter plasmid, treated with the peptide, and NFAT activation monitored. Additionally, RT-qPCR TaqMan array profiling was performed on prostate (PC-3), breast (T-47D), ovarian (OVCAR-3 and SK-OV-3), and pancreatic (BxPC-3 and SU.86.86) cancer cell lines treated with SOR-C13 compared with untreated cells. The TaqMan array panel consisted of 187 genes involved in cancer calcium signalling associated with the MOA of TRPV6 and directly, or indirectly, involved in NFAT signalling. SOR-C13 treatment significantly inhibited NFAT activation (p Citation Format: Christopher Rice, Tyler Lutes, Michelle Davey, Vett Lloyd, Tyson J. MacCormack, John M. Stewart, Dominique Dugourd. The central role of NFAT signalling in the mechanism of action of the TRPV6 oncochannel inhibitor and clinical candidate SOR-C13 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1936.