Lipid News

Targeting sphingolipid metabolism to treat cancer

Christopher Clarke
By Christopher Clarke
November 03, 2020

Bioactive sphingolipids, or SLs, such as ceramide and sphingosine-1-phosphate, long have been implicated in cell death, cell survival and cell growth. This took on greater significance when researchers discovered that SL metabolism is dysregulated in many cancers, leading to the hypothesis that an altered SL balance helps drive the uncontrolled growth and evasion of cell death that are hallmarks of cancer. It also suggested the tantalizing possibility that restoring the balance of SLs could be an effective therapeutic. However, despite considerable effort, the promise of targeting SL metabolism for cancer treatment has yet to be realized fully.  

To date, development of SL-based therapeutics has been pursued in two main ways: using exogenous ceramide, or Cer — the archetypal anti-growth, pro-death SL — and targeting of SL enzymes with increased expression in cancer. While there is considerable evidence that exogenous Cer effectively kills cancer cells in the laboratory, it also affects noncancerous cells. This has been circumvented in part by incorporating Cer into coated nanoliposomes, which have shown promise in preclinical models and are in early clinical trials for safety. However, exogenous Cer also upregulates its own catabolic pathways that can promote a resistance phenotype. As these pathways also can be increased in aggressive cancers, the broader utility of Cer treatments across cancers is unclear.

The best example of the SL enzyme–targeting approach involves the sphingosine kinases 1 and 2, or SK 1 and 2, which are overexpressed in many cancers and whose product, sphingosine-1-phosphate, has been implicated in many pro-tumor biologies, prompting efforts to develop potent and isoform-specific SK inhibitors. However, treatment of many cancer cells with PF-543 — a nanomolar potency SK1 inhibitor — had no effect on cancer cell viability, and studies with other SK inhibitors suggested their anti-cancer efficacy could be due to off-target effects. Thus, researchers are reexamining efforts to develop SK as a general anticancer target.

Sphingosine-1-890x151.jpg
Jynto/Wikimedia Commons
In this ball-and-stick model of the sphingosine-1-phosphate molecule showing the anionic (negatively charged) form, carbon is black, hydrogen is white, oxygen is red, nitrogen is blue and phosphorus is orange.

As our understanding of SL signaling increases, we need to use this knowledge to refine our approach to SL-based therapeutics. For example, there is growing evidence that the same lipid can have different functions depending on where it is generated in the cell — for example, in the endoplasmic reticulum versus the plasma membrane — or the particular species that is produced, such as C16-Cer versus C18-Cer. Thus, more targeted alterations in SL levels may be necessary to achieve the desired anti-cancer response.

Similarly, we need to look beyond a magic-bullet SL therapeutic and consider that different SL targets may be relevant for specific cancers and cancer subtypes — indeed, recent evidence suggests that this might be the case for SKs. Finally, the interconnected nature of the SL metabolism makes it difficult to separate primary driver events from bystander effects. Thus, we need to look beyond enzyme expression to define tumor-specific vulnerabilities in the SL network.

Overall, the potential for cancer therapeutics targeting SL metabolism remains high, particularly as most metabolic outputs are driven enzymatically and are thus highly druggable. We have made strides along the path to translation. We still have a long way to go, but as we gain greater appreciation of the biological roles and regulation of SL, I am confident that ultimately we will succeed.

Christopher Clarke
Christopher Clarke

Christopher Clarke is an assistant professor in the department of medicine and cancer center at Stony Brook University. His research focuses on how deregulation of sphingolipids promotes tumorigenesis.

Join the ASBMB Today mailing list

Sign up to get updates on articles, interviews and events.

Latest in Science

Science highlights or most popular articles

Brain Injury Awareness Month 2021
Health Observance

Brain Injury Awareness Month 2021

March 01, 2021

In the U.S., about 2.8 million people sustain a traumatic brain injury annually. Learn about recent research on TBI-related dementia, dysfunctional mitochondria and other work powering the march toward better therapies.

The evolution of proteins from mysteries to medicines
Essay

The evolution of proteins from mysteries to medicines

February 27, 2021

An essay in observance of National Protein Day.

'Every experiment and every breakthrough matters'
Health Observance

'Every experiment and every breakthrough matters'

February 26, 2021

An interview with NYMC dean Marina K. Holz, who studies a rare disease that affects women of childbearing age.

Progeria: From the unknown to the first FDA-approved treatment
Health Observance

Progeria: From the unknown to the first FDA-approved treatment

February 25, 2021

Hutchinson–Gilford progeria syndrome is a rare, fatal genetic disease that causes premature aging.

Raising awareness and funding for Pompe disease
Health Observance

Raising awareness and funding for Pompe disease

February 25, 2021

Father-turned-advocate has founded multiple organizations to support families and search for better therapies for people with rare lysosomal storage disorder.

A novel approach to septic shock leads to a prospective new therapy
Journal News

A novel approach to septic shock leads to a prospective new therapy

February 23, 2021

A French research team finds new evidence supporting endotoxin removal for treating life-threatening inflammation.