Abstract 5858: Development of a translation elongation inhibitor for the treatment of cancer

Abstract

Abstract Translation is essential for cellular maintenance and growth, as well as survival in response to a variety of stresses. Translation factors are often overexpressed in cancers, and their experimental inhibition has been shown to retard cancer cell growth in a variety of pre-clinical models. Further, clinically relevant forms of cellular stress (e.g. ionizing radiation (IR), hypoxia) result in altered translational programs, and inhibition of translation following such stress results in impaired cellular recovery. Cumulatively these observations suggest that modulation of translation, alone or in combination with genotoxic stress, is of potential therapeutic relevance in oncology. Bouvardin (BVD) is a plant-derived protein synthesis inhibitor that we identified in a screen for enhancers of ionizing radiation (IR). We previously demonstrated that BVD functions as a translation elongation inhibitor by blocking dissociation of elongation factor 2 (eEF2) from the ribosome. In preclinical models of head and neck cancer (HNC) and glioblastoma two cancer indications for which IR is a standard of care, we demonstrated that BVD enhanced clonogenic death induced by IR. Further, BVD enhanced the growth inhibitory effects of IR in HNC tumor xenografts. We show here that a fully synthetic derivative of BVD, SVC112, exhibits strong therapeutic properties alone, and in combination with standards of care, in a variety of solid and hematological cancer models. As an example for solid tumors: in HNC cell lines SVC112 exhibits antiproliferative activity with an average IC50 of ≈150 nM, with no IC50 exceeding 500 nM. In clonogenic assays, physiologically relevant levels of SVC112 robustly synergistically enhance clonogenic death induced by HNC standards of care (e.g. IR and cisplatin). Finally, in cell line based HNC xenografts, SVC112 exhibits antitumorigenic activity as a single agent and enhances the growth inhibitory effects of IR-cisplatin treatment. As an example for hematological cancers: in acute myeloid leukemia (AML) cell lines SVC112 exhibits antiproliferative activity in sensitive cells with an average IC50 of ≈25 nM. Brief exposure to physiologically relevant levels of SVC112 induces rapid and robust apoptosis in sensitive AML cell lines concomitant with the loss of known drivers of AML growth (e.g. MCL-1). Finally, in cell line based AML xenograft models, SVC112 as a single agent induces robust and sustained antiproliferative activity. Cumulatively these data demonstrate that SVC112 mediated inhibition of translation elongation alone, and in combination with existing standards of care, is a potentially promising treatment option for a variety of solid and hematological cancers. This project has been funded in part with Federal funds from the NCI/NIH, Department of Health and Human Services, under Contract No. HHSN261201300021C Citation Format: Nathan Gomes, Barb Frederick, Daniel Gustafson, Bert Pronk, Tin Tin Su. Development of a translation elongation inhibitor for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5858.