Abstract 2910: A novel Sortilin-targeted docetaxel peptide conjugate (TH1902), for the treatment of Sortilin-positive (SORT1+) triple-negative breast cancer

Abstract

Abstract Rational: Breast cancers are comprised of several subtypes that share similar clinicopathological features, but that also exhibit several different biological characteristics. Triple-negative breast cancer (TNBC), which comprises 10-20% of breast cancers, or ~ 170,000 new cases per year worldwide and 70% of the basal-like subtype of breast cancers, is a cancer that does not express estrogen receptor (ER), progesterone receptor (PR) or human epidermal growth factor receptor 2 (HER2). TNBC is considered more aggressive than other breast cancers and more difficult to treat because it still lacks a defined molecular signature. Over the last decade, the targeting of specific cancer cell surface receptors has emerged among the best anticancer strategies. Recently, increased expression of the Sortilin receptor (SORT1) has been reported in TNBC patients. Procedures: Given SORT1 functions in protein internalization, sorting and trafficking, we designed a new anticancer peptide-drug conjugation strategy to target SORT1-positive TNBC by linking Docetaxel to a peptide (TH19P01) that specifically binds to SORT1. Results: In vitro, the Docetaxel-TH19P01 conjugate (TH1902) exerted potent anti-proliferative and anti-migratory activities when tested on TNBC-derived MDA-MB-231 cells. The apoptotic and anti-migratory effects induced by TH1902 were reversed by neurotensin and progranulin, two SORT1 ligands, and upon siRNA-mediated silencing of SORT1. Similar to other taxanes, once internalized in the cancer cell, TH1902 altered microtubule polymerization. In vivo, i.v. administration of TH1902 led to greater tumor regression in a murine MDA-MB-231 xenograft tumor and a dose response was observed for TH1902. When docetaxel was injected i.v. at ¼ of its MTD (3.75 mg/kg/week), it had no apparent effect on tumor burden, compared to animals injected with vehicle alone. In contrast, a strong tumor growth inhibition (100%) and sustained effects were observed in mice treated with TH1902 at 8.75 mg/kg/week (equivalent to docetaxel dose of 3.75 mg/kg/week). At higher dose (35 mg/kg/week), a complete tumor regression was seen in mice, and near-total regression (75%) was found with the 17.5 mg/kg/week dosage. While the decreased neutrophil counts subsequent to administration of docetaxel (15 mg/kg/week) were statistically significant after the first intravenous injection, there was no apparent change in the neutrophil counts for mice which received up to 6 cycles of TH1902 (35 mg/kg/week). Conclusion: Taken together, these pre-clinical data demonstrate high in vivo efficacy and safety of TH1902 against TNBC through a SORT1 receptor-mediated mechanism. This novel approach allows for selective targeting of SORT1-positive breast cancers and makes TH1902 a promising clinical candidate for personalized therapy in the treatment of TNBC. Citation Format: Christian Marsolais, Cyndia Charfi, Michel Demeule, Jean-Christophe Currie, Alain Larocque, Alain Zgheib, Natacha Duquette, Richard Béliveau, Borhane Annabi. A novel Sortilin-targeted docetaxel peptide conjugate (TH1902), for the treatment of Sortilin-positive (SORT1+) triple-negative breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2910.