Abstract C94: Dual downregulation of Myc and AR with a sphingosine kinase-2 inhibitor prevents prostate cancer progression

Abstract

Abstract The bioactive sphingolipid sphingosine-1-phosphate (S1P) drives several hallmark processes of cancer, making the enzymes that synthesize S1P, i.e. sphingosine kinase 1 and 2 (SK1 and SK2), important targets for cancer drug development. ABC294640 is a first-in-class SK2 inhibitor that effectively inhibits cancer cell growth in vitro and in vivo. Given that AR and Myc are two of the most widely implicated oncogenes in prostate cancer (PCa), and that sphingolipids impact signaling by both proteins, the potential for using ABC294640 in the treatment of PCa was evaluated. This study demonstrates that ABC294640 abrogates signaling pathways requisite for PCa growth and proliferation. Key findings validate that ABC294640 treatment of early stage and advanced PCa models downregulate Myc and AR expression and activity. This corresponds with significant inhibition of growth, proliferation, and cell-cycle progression. Finally, oral administration of ABC294640 was found to dramatically impede xenograft tumor growth. Together, these results support the hypotheses that SK2 activity is required for PCa function and that ABC294640 represents a new pharmacological agent for treatment of early stage and aggressive PCa. Citation Format: Randy S. Schrecengost, Staci Keller, Matthew Schiewer, Karen Knudsen, Charles Smith. Dual downregulation of Myc and AR with a sphingosine kinase-2 inhibitor prevents prostate cancer progression. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C94.