Abstract B18: EL102: A novel dual inhibitor which demonstrates additive prostate cancer inhibitory activity in combination with docetaxel in vitro and in mouse models

Abstract

Abstract Introduction: EL102, a novel toluidine sulphonamide, was developed from a phenotypic screen to develop novel small molecule inhibitors of the hypoxia signalling cascade. It is a dual-inhibitor of apoptosis and angiogenesis, and exerts its action though the inhibition of Hif1 alpha induced hypoxic signalling pathways and induction of the Caspase 3/7 apoptotic cascade. The drug has equal activity against normoxic and hypoxic tumour cells indicating that it may be equally active in these different tumour compartments. Hypothesis: We hypothesize that the dual inhibition of anti-apoptotic and angiogenic pathway is a viable therapeutic strategy for the treatment of prostate cancer, and may be additive to taxane-based chemotherapeutic strategies. Experimental Procedures: We assessed the ability of EL102 to inhibit prostate cancer cell proliferation and cell motility in vitro in normal prostate RWPE1, androgen dependent CRW22 and its androgen independent variant 22Rv2,and the metastatic prostate cancer cell lines PC3 and DU145. Mechanistic studies included the effects of EL102 on VEGF, IL-6 and Il-8 secretion and ability to inhibit Hif1a expression. Additionally we assessed the activity of EL102 in combination with docetaxel in vitro and in murine models using CRW22 xenografts. Results: Prostate cancer cell lines are sensitive to EL102 with IC50s for inhibition of cell proliferation in the region of 10-50nM. Of particular interest was the comparable sensitivity of the androgen independent 22Rv1 cell line and it androgen dependent parent cell line CRW22, suggesting that EL102 may also be active in hormone refractory prostate cancer. Additionally we demonstrate dose response for the inhibition of cell motility in the metastatic prostate cancer cell lines DU145. In CRW22 murine mouse models treatment with EL102 resulted in significantly decreased tumour volume compared to control. A docetaxel and EL102 combination arm demonstrated the greater inhibition of tumour growth than EL102 or docetaxel alone. Conclusions: EL102 is a potential therapeutic agent for the treatment of prostate cancer, as a single agent or in combination with docetaxel. The histopathology of tumours from mice treated with EL102 in combination with docetaxel on Ki-67, Hif1 alpha, VEGF and apoptosis in vivo is evaluated. Future studies will establish the efficacy of EL102 in a PC3 metastatic prostate cancer mouse model. Additionally the ability of EL102 to circumvent the classic drug resistance mechanisms MDR1, MRP1 and BCRP, and overcome taxane resistance will be presented. Citation Format: Aidan Toner, Fiona McLaughlin, Jill McMahon, Francis J. Giles, Frank Sullivan, Laura Breen, Martin Clynes, Joe D. Lewis, Sharon A. Glynn. EL102: A novel dual inhibitor which demonstrates additive prostate cancer inhibitory activity in combination with docetaxel in vitro and in mouse models [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B18.