Abstract 1313: TH1902, a docetaxel peptide-drug conjugate, shows pre-clinical efficacy in several Sortilin-positive (SORT1+) cancers

Abstract

Abstract One strategy to achieve greater selectivity of anticancer drug to cancer cells is the conjugation of cytotoxic agents to peptide ligands that selectively target receptors abundantly expressed in these tumor cells. Recently, increased expression of sortilin (SORT1), a scavenging receptor, has been observed in various cancers including breast, ovarian, endometrial, skin, colorectal and pancreatic cancers. In light of these SORT1 levels, we developed a peptide conjugation platform to target SORT1 and to increase cell selectivity and internalization of anticancer agents. Docetaxel was conjugated to a sortilin-binding proprietary peptide (TH19P01). High in vitro intracellular internalization of TH19P01 in TNBC cells was first confirmed and was reduced when SORT1 expression was silenced using siRNA or upon competition with the SORT1 ligands neurotensin and progranulin. Significant in vitro intracellular delivery of the docetaxel-TH19P01 conjugate (TH1902) was observed in SORT1+ cancer cell lines while maintaining efficient docetaxel cytotoxic mechanism. TH1902 further exerted potent anti-proliferative and anti-migratory activities when tested on TNBC-derived MDA-MB-231 cells. TH1902 also triggered faster and more potent apoptotic cell death than did docetaxel. Pre-clinical in vivo studies were performed in human SORT1+ tumor xenografts grown in mice including TNBC (MDA-MB-231 and HCC-70), melanoma (SK-MEL-28), colorectal (HT-29) and pancreatic (PANC-1) cancer models. Mice were treated with either TH1902 or docetaxel by IV bolus injections at equivalent doses of docetaxel (MTD or ¼ MTD). In all cases, TH1902 showed more potent inhibition than Docetaxel. These results strongly support future clinical development of TH1902 as novel therapeutics in SORT1+ cancers. Citation Format: Christian Marsolais, Jean-Christophe Currie, Michel Demeule, Cyndia Charfi, Alain Larocque, Alain Zgheib, Richard Béliveau, Borhane Annabi. TH1902, a docetaxel peptide-drug conjugate, shows pre-clinical efficacy in several Sortilin-positive (SORT1+) cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1313.