Chapter Twelve - Novel Sphingolipid-Based Cancer Therapeutics in the Personalized Medicine Era

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Abstract

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 and Kolesnick, 2017, Morad and Cabot, 2013, Newton et al., 2015, Ogretmen, 2018, Ryland et al., 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.

Section snippets

Chemotherapy

Chemotherapeutic or cytotoxic agents are drugs commonly used as standard of care for multiple types of cancers due to their ability to kill or damage highly proliferative cells. These agents are usually divided into classes based on their mechanisms of action, and, strikingly, a wide range of these classes have been described as leading to accumulation of sphingolipids (particularly ceramide) in cells. As shown in Fig. 1, we depict the steady state accumulation of endogenous ceramide via chemo-

Current Landscape of Inhibitors of Sphingolipid Metabolism

Sphingolipids are vital to normal cell function and thus the dysregulation of the enzymes responsible for their production and maintenance can lead to a number of diseases, including cancer. As such, the ability to regulate the activity of these enzymes using inhibitors or activators is important for developing novel treatments for diseases in which sphingolipid imbalance occurs. Thus, the search for effective inhibitors for the enzymes that decrease ceramide levels are worth exploring. The

Methods for Delivery of Sphingolipids and Mimetics to Cells

Instead of relying on increasing “flow through the faucets or clogging the drains,” we can also simply add water to the sink externally to overflow the system (Fig. 1). Over the past 10 to 15 years, a number of approaches have been developed to enhance delivery of sphingolipids and analogues directly to cells in an effort to alter cell physiology, usually to disrupt the growth of tumor cells. Of these delivered sphingolipids, the most common is ceramide, with numerous chemical modifications and

Sphingolipids Synergize With Chemotherapeutics

Recent studies have shown that elevating endogenous levels of ceramide by opening metabolic “faucets” or closing some of the enzymatic “drains” can augment the efficacy of conventional treatments in cancer. In addition, exogenous delivery platforms for sphingolipid mimetics can also elevate endogenous ceramide levels (Fig. 1). This section will review underlying combinatorial/synergistic cytotoxic mechanisms between elevated ceramide levels/decreased S1P levels and chemotherapeutic regulation

Conclusion

In the ever-growing quest to better understand the basis of cancer, numerous tools and collaborative efforts have emerged as powerful initiatives for research and medicine. The Cancer Genome Atlas represents one of the largest such endeavors, chronicling patient samples and organizing them by cancer type, gene expression, RNA profile, and mutation profile, among others. With the increasing sensitivity and selectivity as well as availability of mass spectrometry devices capable of creating full

Acknowledgments

This work was supported by National Institutes of Health Grants 5 P01 CA171983 and R01s CA208396, CA167535 to MK; R01 GM043880 to SS.

Conflict of Interest

Penn State Research Foundation has licensed ceramide nanoliposomes and other sphingolipid-based nanoscale therapeutics to Keystone Nano, Inc (State College, PA). MK is Chief Medical Officer and cofounder of Keystone Nano, Inc.

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