Potential Use of Sphingosine Kinase-2 Selective Inhibitors for the Treatment of Multiple Myeloma

Abstract 5105

Multiple myeloma (MM) is the second most common hematological malignancy in the United States and accounts for ∼10,600 deaths annually. Despite the widespread use of several highly active chemotherapy agent (thalidomide, lenalidomide and bortezomib) and the incorporation of autologous hematopoietic stem cell transplantation, MM remains an incurable disease, suggesting the need for a better understanding of the disease's molecular pathways and for the development of novel agents. Sphingolipid metabolism is being increasingly recognized as a key pathway in cancer biology. Among a series of sphingolipid-metabolizing enzymes, sphingosine kinases (SK-1 and -2) are considered to be key regulators of cancer cell proliferation. SK phosphorylates sphingosine to sphingosine-1-phosphate (S1P) and affects the delicate balance between apoptotic ceramide/sphingosine and proliferative S1P. SKs are highly expressed in several solid tumors including pancreatic cancer and ovarian cancer. Currently, however, very little is known about how the SK is expressed in MM, and how sphingolipids respond to drugs targeting SK. We hypothesize that SKs play important roles in the pathogenesis of MM, thus providing a novel target for the treatment of MM. Apogee Biotechnology Corporation has generated new, orally bioavailable small molecule SK inhibitors that have in vitro and in vivo activity in a variety of models of cancer and inflammatory diseases. Several advantages of these SK inhibitors over other anti-MM drugs include: the role of the target in multiple key pathways driving MM; the low toxicity observed in GLP toxicology testing; the oral bioavailability that will simplify administration; and the ability to be combined with the standard drugs for MM (i.e, bortezomib). ABC294640, a SK2-selective inhibitor has recently entered single-agent clinical testing in advanced pancreatic cancer at our institution. In the current study, we investigated the expression patterns of SK2 in myeloma cells and the therapeutic potential of ABC294640 in the treatment of MM. We found that SK2 is highly expressed in several myeloma cell lines and in primary human CD138+ myeloma cells. Compared to the A498 human kidney adenocarcinoma cell line, the expression levels of SK2 mRNA were 1.4–12 fold higher in myeloma cell lines. The expression level of SK2 mRNA was > 62 fold higher in primary human CD138+ myeloma cells, compared to CD138- cells (n = 4). When myeloma cells were treated with ABC294640, cell proliferation was effectively inhibited with IC₅₀ of ∼20 μM, including steroid resistant MM1.R myeloma cells. The degree of cell growth inhibition by ABC294640 correlated well with the expression level of SK2 mRNA in the myeloma cells. We also found that ABC294640 induces PARP cleavage and caspase 3 and 9 activation, indicating that the SK2 inhibitor induces apoptotic cell death. We are currently testing the effects of ABC294640 alone and in combination with dexamethasone or proteasome inhibitors in vivo in the XBP-1s transgenic MM model. Preclinical toxicities of the drug combinations will also be determined in the mouse models. Our studies provide the first evidence of SK2 in the pathogenesis of MM, and suggest excellent therapeutic potential of SK2-selective inhibitors for the treatment of MM.

This work is supported by MUSC Hollings Cancer Center Startup Fund, Hollings Cancer Center ACS IRG, and ASCO Conquer Cancer Foundation Career Development Award