Use of acid sphingomyelinase for cancer therapy.

Acid sphingomyelinase (ASM) is a lipid hydrolase that cleaves the sphingolipid, sphingomyelin, into ceramide. Mutations in the ASM gene (SMPD1) result in the rare lysosomal storage disorder, Niemann-Pick disease (NPD). In addition to its role in NPD, over the past two decades, the importance of sphingolipids, and ASM in particular, in normal physiology and the pathophysiology of numerous common diseases also has become known. For example, altered sphingolipid metabolism occurs in many cancers, generally reducing the levels of the pro-apoptotic lipid, ceramide, and/or elevating the levels of the proliferative lipid, sphingosine-1-phosphate (S1P). These changes likely contribute to the tumorigenicity and/or metastatic capacity of the cancer. In addition, many cancer therapies induce ceramide-mediated death, and cancer cells have evolved novel mechanisms to overcome this effect. In the present review, we discuss sphingolipid metabolism in cancer, and specifically the potential for pharmacological modulation using ASM. Of note, recombinant human ASM (rhASM) has been produced for human use and is being evaluated as a treatment for NPD. Thus, its use for cancer therapy could be rapidly evaluated in the clinic after appropriate animal model studies have been completed. As this enzyme was initially studied in the context of NPD, we start with a brief overview of the history of ASM and NPD, followed by a discussion of the role of ASM in cancer biology, and then summarize emerging preclinical efficacy studies using rhASM as an adjunct in the treatment of solid tumors.