Abstract 1649: Potent anticancer activity of an orally bioavailable small molecule, ON 013100, and its water soluble derivative, briciclib, a clinical-stage eIF4E-targeted agent
Authors: Jasani Neel , Desai Bina , Betzu Justine M. , Dichwalkar Tanmay , Bapat Samhita , Rajadhayksha V. J. , Hoffman Benjamin S. , Maniar Manoj , Sehdev Vikas 
Published: August 2015

Abstract
Introduction: Eukaryotic translation initiation factor 4E (eIF4E) is a master regulator that controls translation of mRNA in mammalian cells. eIF4E is a proto-oncogene that promotes translation of several genes essential for cellular proliferation (cyclin D1, c-Myc, mTOR), survival (Akt, survivin), angiogenesis (VEGF), and metastasis (MMP9). Overexpression of eIF4E has been observed in almost all major groups of cancers and has been shown to induce increased expression of cyclin D1 and c-Myc. Briciclib is a small molecule, water soluble derivative of ON 013100 that binds to eIF4E. An intravenous formulation of briciclib is currently being investigated in a Phase 1 clinical trial. Recent advancements in formulation technology have made feasible a stable, orally bioavailable version of ON 013100, which may allow for more convenient administration. In this study we investigated and compared the anticancer activity of briciclib to ON 013100. We determined the susceptibility of various breast, mantle cell leukemia (MCL), gastric, and esophageal cancer cell lines to treatment with briciclib or ON 013100. In addition, we investigated the effect of briciclib and ON 013100 on expression of markers associated with eIF4E activity (cyclin D1 and c-Myc) and apoptosis (P53 and Cleaved Caspase 3). Methods: MTT cell viability assays, Western blot analysis, and ELISA assays were used to evaluate cellular viability, survival, and protein expression levels. Results: Briciclib and ON 013100 inhibited the proliferation of MCL (JEKO-1 and MINO), breast (MCF7 and MDA-MB-231), gastric (AGS), and esophageal (OE19, OE33, and FLO-1) cancer cell lines at nanomolar concentrations (Briciclib: GI50 = 9.8 - 12.2 nM; ON 013100 GI50 = 6.7 - 11.2 nM). By comparison, briciclib and ON 013100 were relatively non-toxic to normal endothelial cells. Western blot analysis indicated that treatment with briciclib or ON 013100 significantly reduced the expression of cyclin D1 and c-Myc in breast and MCL cancer cell lines within 8 hours and in a dose-dependent manner. These observations were supported by ELISA analysis of cyclin D1 and c-Myc protein levels. Furthermore, treatment with these agents enhanced the expression of P53 and Cleaved Caspase 3 pro-apoptotic proteins in breast and MCL cancer cell lines. Our ongoing tumor xenograft experiments are in agreement with the aforementioned in vitro observations. Conclusions: Our findings suggest that both an orally bioavailable ON 013100, and its water soluble derivative, briciclib, have the same novel mechanism of action involving translation. Our in vitro and in vivo data demonstrate the potential of briciclib in targeting eIF4E for hematopoietic and solid cancers and the possibility for developing an oral version of this promising clinical agent.
Citation Format: Neel Jasani, Bina Desai, Justine M. Betzu, Tanmay Dichwalkar, Samhita Bapat, V. J. Rajadhayksha, Benjamin S. Hoffman, Manoj Maniar, Vikas Sehdev. Potent anticancer activity of an orally bioavailable small molecule, ON 013100, and its water soluble derivative, briciclib, a clinical-stage eIF4E-targeted agent. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1649. doi:10.1158/1538-7445.AM2015-1649