Abstract 6362: TH1901, a novel curcumin-peptide conjugate for the treatment of Sortilin-positive (SORT1+) cancer

Rational: Phytochemicals are compounds found in plant foods that can help prevent the occurrence of chronic diseases like cancer. Several studies, over the last decade on the impact of phytochemicals in cancer treatment, have provided experimental evidence that curcumin contains antiproliferative, antiangiogenic, and apoptotic properties. Further evidence suggested that curcumin also suppresses tumor/colon cancer cell progression and angiogenesis by stimulating apoptosis and regulating immune response. Increased expression of the scavenging receptor Sortilin (SORT1), has been clinically observed in numerous invasive tumor biopsies. Procedures: In light of this, we developed a peptide conjugation platform and a new SORT1 receptor-mediated strategy to increase cell targeting selectivity and cell delivery of anticancer agents. As a proof-of-concept for phytochemicals, curcumin was conjugated to a SORT1-binding proprietary peptide (TH19P01). Curcumin-TH19P01 conjugate (TH1901) and unconjugated curcumin were tested on the proliferation of various cancer cells. Results: TH1901 showed a stronger anti-proliferation activity against cancer cells, with IC50 values up to 100-fold greater when compared to unconjugated curcumin. In addition, higher accumulation of fluorescence was detected for TH1901 indicating a more efficient cell internalization and release of curcumin from the conjugate. TH1901 uptake was reduced in the presence of SORT1 ligands neurotensin and progranulin as well as of free peptide confirming a preferential SORT1-mediated uptake of TH1901 in ES-2 ovarian cancer cells. Fluorescence microscopy showed that, in contrast to unconjugated curcumin, TH1901 induced cell apoptosis, and showed a stronger effect than unconjugated curcumin on TNF-alpha-induced intracellular signaling pathways involved in pro-inflammation processes. Interestingly, conjugation of curcumin also increased its in vitro stability in solution. In vivo, intraperitoneal administration of TH1901 (60 mg/kg/twice a week) inhibited growth of SORT1+ HT-29 colorectal cancer cell subcutaneous xenograft tumors, whereas at an equivalent dose unconjugated curcumin (15 mg/kg/twice a week) had no effect. Conclusion: Overall, these proof-of-concept experiments support the future development of this flexible and innovative platform to generate novel anticancer treatments. Citation Format: Borhane Annabi, Michel Demeule, Jean-Christophe Currie, Alain Larocque, Alain Zgheib, Christian Marsolais, Richard Beliveau. TH1901, a novel curcumin-peptide conjugate for the treatment of Sortilin-positive (SORT1+) 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 6362.