Abstract LB-051: Cancer cell binding, internalization and intracellular localization of a novel therapeutic peptide SOR-C13 targeting the TRPV6 oncochannel

• Published in: Cancer research (Chicago, Ill.) Vol. 76; no. 14_Supplement; p. LB-051
• Main Authors: Davey, Michelle, Dugourd, Dominique, Lutes, Tyler, Rice, Christopher, Gormley, Sean, St. Pierre, Stephanie, Stewart, John M.
• Format: Journal Article
• Language: English
• Published: 15.07.2016
• DOI: 10.1158/1538-7445.AM2016-LB-051
• ISSN: 0008-5472

Abstract SOR-C13, a 13-mer peptide derived from soricidin, the paralytic protein component of saliva of the Northern Short-tailed shrew, has recently completed a phase I clinical trial for the treatment of epithelial-derived cancers. SOR-C13 specifically targets and inhibits the TRPV6 calcium channel - a recognized oncochannel over-expressed in a number of epithelial cancers (e.g. breast, ovarian, prostate). SOR-C13 is the first TRPV6-targeting drug to enter clinical development. Xenograft and fluorescent imaging studies provide in vivo evidence of SOR-C13 efficacy in a range of epithelial tumors as well as SOR-C13's preferential accumulation at tumour sites. To demonstrate the specificity of the peptide for TRPV6 and determine its fate, modified SOR-C13 peptide was labeled with fluorescein to enable monitoring of cellular binding and internalization in high versus low TRPV6 cancer cell lines. Various organelle-specific fluorescent trackers for nuclei, actins, lysosomes, and endoplasmic reticula were paired with labeled SOR-C13 peptides and anti-TRPV6 antibody in fluorescence imaging studies to monitor intracellular trafficking. Rapid peptide binding and internalization was observed on incubation of fluorescently labeled SOR-C13 with a breast cancer cell line (T-47D) expressing high levels of the ion channel. Significantly less SOR-C13 binding was observed in an ovarian cancer cell line (SKOV-3) with low TRPV6 levels. Fluorescently labeled SOR-C13 scramble peptide was included as a control and did not bind to high TRPV6 cells. Co-localization studies did not demonstrate a clear association of the fluorescently labeled SOR-C13 with lysosomes, the ER or actin. This study demonstrates that SOR-C13 not only specifically binds to TRPV6-expressing cancer cells according to their level of TRPV6 expression but is also internalized. The correlation of TRPV6 expression in tumors and clinical efficacy will be evaluated during the next SOR-C13 clinical trials. Additionally, these results set the stage for further development of SOR-C13-based peptide drug conjugates for TRPV6 targeted anti-cancer therapies. Citation Format: Michelle Davey, Dominique Dugourd, Tyler Lutes, Christopher Rice, Sean Gormley, Stephanie St. Pierre, John M. Stewart. Cancer cell binding, internalization and intracellular localization of a novel therapeutic peptide SOR-C13 targeting the TRPV6 oncochannel. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-051.