Abstract 323: SKI-178, a single agent co-targeting sphingosine kinase 1 and microtubule dynamics, as a therapeutic strategy for treatment of acute myeloid leukemia

Acute myeloid leukemia (AML) is a heterogeneous and rapidly progressing blood cell cancer caused by numerous cytogenetic alterations. Although significant improvement in treatment of AML has been made, the unfortunate reality is that currently available treatments are largely ineffective for most AML patients. Thus, there is a critical need for new therapeutic targets and agents for the treatment of AML. The sphingolipid metabolic pathway is an untapped source of new therapeutic targets for the treatment of AML. Sphingosine Kinase 1 (SphK1) plays a central role in the sphingolipid metabolic pathway as the key enzyme regulating the intracellular equilibrium between pro-apoptotic Ceramide (Cer) and pro-mitogenic/pro-survival Sphingosine-1-phosphate (S1P), a.k.a. the “Sphingolipid Rheostat”. As SphK1 activity increases in the cell, pro-mitogenic/pro-survival S1P signaling predominates and AML cells become dependent upon S1P signaling (non-oncogene addiction), while depletion of Cer levels makes them more resistant to chemotherapies. We previously developed a novel SphK1-selective inhibitor (SKI-178) that is potently cytotoxic to multiple AML cell lines including multi-drug resistant lines. Our recent, thorough examination of the apoptotic mechanism-of-action of SKI-178, including direct target engagement assays employing the Cellular Thermal Shift Assay (CETSA) revealed that SKI-178 also acts as a colchicine binding site directed microtubule disrupting agent (MDA). Numerous studies have demonstrated that agents that promote Cer accumulation, including SphK inhibitors, synergistically induce apoptosis, in combination with MDAs by the simultaneous activation of pro-apoptotic Bcl-2 family proteins and inhibition of anti-apoptotic Bcl-2 family proteins, respectively. SKI-178 uniquely accomplishes these two separate cellular effects as a single agent. We examined the therapeutic efficacy of SKI-178 in three mouse models of AML. Using a retro-viral transduction model of the MLL/AF9 t(9;11)(p22;q23) translocation, we have shown that SphK1 is necessary for the development of MLL/AF9-driven AML and that SKI-178 effectively induces complete remission of AML in this model system. Separately, in a human AML cell line (MOLM-13; MLL/AF9+, FLT3-ITD) xenograft model, SKI-178 significantly extended survival relative to vehicle controls. Lastly, employing a Patient Derived Xenograft model of a human primary AML sample (FLT3-ITD, NPM1+), SKI-178 also significantly extended survival relative to vehicle treated cohorts. In all 3 models, SKI-178 was well tolerated and did not affect normal hematopoiesis. Together, these data demonstrate the therapeutic efficacy of a strategy co-targeting SphK1 inhibition and microtubule dynamics and suggest that SKI-178 should be further developed as a novel therapeutic agent for AML. Citation Format: Taryn E. Dick, Jeremy A. Hengst, Laura M. Geffert, Robert F. Paulson, Hong-Gang Wang, David F. Claxton, Mark Kester, Thomas P. Loughran, Jong K. Yun. SKI-178, a single agent co-targeting sphingosine kinase 1 and microtubule dynamics, as a therapeutic strategy for treatment of acute myeloid leukemia. [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 323.