Abstract 1812: XCE853: A novel PDI inhibitor that inhibits proliferation of human tumor cells in vitro, ex-vivo and in vivo

Abstract

Abstract XCE853 was originally identified within a family of synthetic compounds displaying a preferential antiproliferative activity on drug resistant human cancer cells (Gutmann et al, AACR annual meeting, 2013). XCE853 induced an irreversible cytolysis of human tumor cells after a short in vitro exposure independently of efflux pumps leading to a tumor cell death by autophagy and particles release (vesicles or protein aggregates). The interest for XCE853 has been reinforced by three in vitro observations: 1) XCE853 inhibits the recombinant human enzyme PDI recognized as one novel target linked to drug resistance 2) XCE853 has a unique antiproliferative profile compared to the NCI database compounds when using the NCI Compare assay and 3) XCE853 has no activity on human normal prostate cells even at high concentrations whereas XCE shows an IC50 in the nanomolar range on human tumoral cells. In addition, the ex-vivo approach using fresh human tumor explants cultivated in 3 dimensions with low concentrations of XCE853 has shown a strong decrease of the proliferation (KI-67 labeling) with an apoptosis induction (Caspase-3 labeling) of Head & Neck cancers following 24h of exposure. Finally, XCE853 which displayed an excellent oral bioavailability in mouse is able to block growth of human ovarian cancer using in vivo xenograft model leading to a complete tumor growth arrest even after the stop of the treatment. Altogether, these data support further efforts on this drug candidate to initiate the preclinical studies and to define the most relevant human tumor types. Citation Format: Gregoire P. Prevost, Shili Xu, Marine Garrido, Maria Serova, Olivier DE Vewer, Christian Gespach, Jean-François Briand, Annemilaï Tijeras-Raballand, Mathieu Gutmann, An Hendrix, Michele Sabbah, Anne Chachereau, Armand de Gramont, Nouri Neamati, Denis Carniato, Marc-Henry Pitty, Paul Foster. XCE853: A novel PDI inhibitor that inhibits proliferation of human tumor cells in vitro, ex-vivo and in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1812. doi:10.1158/1538-7445.AM2014-1812