Abstract B24: Development of a radiation modulator that functions via translation inhibition

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, hypoxia) result in altered translational programs. Inhibition of translation following such stress results in impaired cellular recovery. Taken together 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) in D. melanogaster. 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 glioma, 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 in mice. We show here that a fully synthetic derivative of BVD, SVC112, exhibits promising therapeutic properties in tissue culture and xenograft models of HNC. Like BVD, SVC112 inhibits general de novo protein synthesis in cell culture. In a panel of 19 HNC cell lines SVC112 exhibits antiproliferative activity with an average IC50 of ~160 nM, with no IC50 exceeding 500 nM. Combinations of SVC112 and IR dose-response curves in HNC cells yield average combination-index (CI) values generally lower than 1, especially in maximally tolerated dose ranges. CI values of 1 are indicative of additive interactions, while CI values <1 are indicative of synergy between two agents. Further, in clonogenic assays physiologically achievable levels of SVC112 consistently exhibit dose modifying factors (DMF) of >1 in HNC cells, when combined with a range of clinically relevant IR doses. DMF values of 1 are indicative of additive interactions, while DMF values >1 indicate synergistic enhancement of IR mediated clonogenic death. Additionally in clonogenic assays, SVC112 enhances cisplatin-IR mediated clonogenic death. Finally, SVC112 enhances the growth inhibitory effects of IR-cisplatin treatment (alone and in combination) in HNC tumor xenografts in mice. Taken together these data demonstrate that inhibition of translation elongation in combination with existing standards of care is a potentially promising treatment option for cancers of the head and neck. *This project has been funded in whole or 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, Ryan Hansen, Gan Zhang, Daniel Gustafson, Gijsbertus Pronk, Tin Tin Su. Development of a radiation modulator that functions via translation inhibition. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B24.