Abstract A194: OTX008, a small molecule that inhibits galectin-1, potentiates the in vitro effects of cytotoxic and targeted agents in several human cancer models.

Abstract

Abstract Background: Galectin-1 is a glycoprotein involved in various stages of tumorigenesis and lately described as a promising anti-cancer target. Previously, we demonstrated that a novel calix[4]arene small molecule, OTX008, decreased galectin-1 expression, inhibited cell proliferation and induced anti-tumor activity in human tumor xenografts (EORTC 2011, Abstract n°C76). This in vitro study aimed to investigate antiproliferative effects of OTX008 with various cytotoxic and targeted agents in colon, head & neck (H&N) and hepatocellular (HCC) carcinoma models. Material and Methods: Combination effects were evaluated in established human colon (Colo205-S, Colo205-R, HT29 and HCT116), H&N (SQ20B, HEP2, SCC61 and Detroit) and HCC (SKHEP1, HEP3B, HEPG2 and JHH6) cancer cell lines by MTT assay. Simultaneous and sequential schedules of administration were tested. Combination Index (CI) was determined by median effect plot analysis using CalcuSyn software (Chou & Talalay analysis). Briefly, CI<1 means synergistic effects, CI=1 means additivity and CI>1 means antagonist effects. Results: Exposure to OTX008 and cisplatin exerted synergistic effects in WT K-RAS colon cancer cells and antagonist/additive effects in mutated K-RAS colon cancer cells; whereas synergy was observed in 3 out of 4 H&N cell lines. Interestingly, OTX008 and oxaliplatin combination was found synergistic in all colon and H&N cell lines tested regardless of the administration schedule, while it was at least additive in HCC cell lines. OTX008 and carboplatin combination showed antagonist effects in H&N cells. Sequential administration of OTX008 with 5-FU, 5’-DFUR or gemcitabine in colon cancer cell lines displayed synergistic effects, whereas, OTX008 and gemcitabine combination showed additive effects in HCC cells. Interestingly, all tested schedules of administration combining OTX008 and docetaxel were synergistic in both colon and H&N cell lines. OTX008 combination with targeted therapy agents: OTX008 given prior to sunitinib displayed synergistic effects while the reverse sequence showed at least additivity in all colon, H&N and HCC cancer cell lines. Unlike sunitinib, sorafenib and OTX008 exhibited antagonist/additive effects in colon and HCC cell lines. In addition, treatment sequence of OTX008 before regorafenib showed synergistic effects in all tested colon cancer cell lines. Conclusion: Taken together, our results indicate that OTX008 was able to enhance in vitro antiproliferative effects of the tested cytotoxic and targeted therapy agents including cisplatin, oxaliplatin, docetaxel, 5-FU, 5’-DFUR, sunitinib, and regorafenib, indicating that combinations maybe considered an important aspect of its clinical development. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A194. Citation Format: Lucile Astorgues-xerri, Maria Eugenia Riveiro, Kay Noel, Esteban Cvitkovic, Mohamed Bekradda, Maria Serova, Sandrine Faivre, Eric Raymond. OTX008, a small molecule that inhibits galectin-1, potentiates the in vitro effects of cytotoxic and targeted agents in several human cancer models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A194.