Abstract 3030: CT179: A novel small molecule Olig2 inhibitor for the treatment of glioblastoma

Abstract

Glioblastoma (GBM) is an orphan disease with a high unmet medical need. Despite optimal treatment, the median survival is only 12 to 15 months in GBM patients of which only 4% achieve 5-year survival. OLIG2 is a transcription factor that is almost exclusively expressed in the CNS that has been linked to the tumorigenesis of GBM cells and their resistance to radiotherapy. Importantly OLIG2 is a key transcription factor that maintains the stemness of the glial stem cells, drives proliferation and invasion and recurrent tumor growth. Inhibitors of this pathway are therefore of interest as potential treatments for this unmet need. CT-179 is a small molecule inhibitor that was initially designed to prevent homodimerization of Olig2. CT-179 is highly cytotoxic to OLIG2 expressing GBM cells with a high therapeutic index for non-OLIG2 expressing cell types. This inhibitor demonstrates functional inhibition of the OLIG2 pathway through specific reduction in nuclear Olig2 protein levels in treated cells. A cell pathway analysis indicates that CT-179 impacts GBM proliferation through cell cycle arrest and induction of apoptosis. Secondarily an immunosuppression mechanism-of-action may also be relevant. CT-179 penetrates the CNS to attain high brain concentrations at levels far in excess of its cytotoxicity to GBM cells. Efficacy studies reveal dose dependent reductions of tumor growth which is enhanced with radiotherapy. CT-179 demonstrates impressive extension of survival in orthotopic human PDX GBM. Safety studies indicate that there is a large therapeutic window. The compound has a long half-life, low metabolism and has excellent formulation properties and PK supporting once per day oral dosing. CT-179 show promise as both a cytotoxic agent and as potential radiosensitizer for use in the treatment of GBM. Citation Format: Gordon Alton, Graham Beaton, Susan Knowles, Greg Stein, Rajesh Mukthavaam, Santosh Kesari. CT179: A novel small molecule Olig2 inhibitor for the treatment of glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3030.