Novel Sphingolipid-Based Cancer Therapeutics in the Personalized Medicine Era

Sphingolipids are bioactive lipids that participate in a wide variety of biological mechanisms, including cell death and proliferation. The myriad of pro-death and pro-survival cellular pathways involving sphingolipids provide a plethora of opportunities for dysregulation in cancers. In recent years, modulation of these sphingolipid metabolic pathways has been in the forefront of drug discovery for cancer therapeutics. About two decades ago, researchers first showed that standard of care treatments, e.g., chemotherapeutics and radiation, modulate sphingolipid metabolism to increase endogenous ceramides, which kill cancer cells. Strikingly, resistance to these treatments has also been linked to altered sphingolipid metabolism, favoring lipid species that ultimately lead to cell survival. To this end, many inhibitors of sphingolipid metabolism have been developed to further define not only our understanding of these pathways but also to potentially serve as therapeutic interventions. Therefore, understanding how to better use these new drugs that target sphingolipid metabolism, either alone or in combination with current cancer treatments, holds great potential for cancer control. While sphingolipids in cancer have been reviewed previously (Hannun & Obeid, 2018; Lee & Kolesnick, 2017; Morad & Cabot, 2013; Newton, Lima, Maceyka, & Spiegel, 2015; Ogretmen, 2018; Ryland, Fox, Liu, Loughran, & Kester, 2011) in this chapter, we present a comprehensive review on how standard of care therapeutics affects sphingolipid metabolism, the current landscape of sphingolipid inhibitors, and the clinical utility of sphingolipid-based cancer therapeutics.