Targeting Sphingosine Kinase in AML

Little improvement in clinical outcomes has been achieved in acute myeloid leukemia (AML) patients over the past several decades. With this need in mind, we have initiated this project with the overall goal of validating Sphingosine Kinase 1 (SphKI) as a novel molecular target and further developing our novel SphKI-selective inhibitor (SKI-178) as an effective therapeutic agent for AML. SphKI, which can function as a pro-tumorigenic factor, is a signaling lipid kinase that catalyzes the formation of pro-mitogenic sphingosine-1-phosphate (S1P) at the expense of pro-apoptotic ceramide. Accumulating evidence indicates that SphKI is a protein commonly over-expressed in AML cells. Studies showed that upregulation of this lipid kinase alters the balance of sphingoiipid signaling in AML cells in ways that promote AML cell growth/proliferation, while simultaneously blocking apoptotic cell death. On the other hand, evidence shows that inhibition of SphKI expression/activity in AML cells blocks pro-mitogenic/prosurvival SIP signaling and concomitantly induces anti-mitogenic/pro-apoptotic ceramide signaling, resulting in apoptotic cell death. These findings support that targeting SphKI is an exciting new therapeutic approach in AML. As such, we have identified and optimized a SphKI-selective small molecule inhibitor (SKI-178). The preliminary evidence indicates that inhibition of SphKI activity by SKI- 178 results in AML cell apoptosis in a ceramide-dependent manner. Based on these findings and other evidence, it is hypothesized that SKI-178 induces AML cell apoptosis by activating a Cer-dependent JNK/Bcl-2/Caspase-3/7 signaling pathway. The specific goals of the proposed study are to: A) elucidate the mechanism-of-action (MOA) by which SKI-178 induces AML cell apoptosis by modulating sphingoiipid metabolite formation, thus validating SphKI as a novel molecular target in AML and B) establish the efficacy and safety profile of SKI-178 using both primary human AML (hAML) cells and in vivo mouse AML model systems. To accomplish these goals, we have developed a team of investigators composed of basic scientists with expertise in SphKI signaling and cancer biology, synthetic chemists with expertise in medicinal chemistry and clinical scientists with expertise in AML. The results obtained from the in vitro and in vivo assessment of our novel SphKI-selective inhibitor, SKI-178, will provide insights into the improvement of pharmacological therapeutic agents that selectively target SphKI in AML.