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Keyword: sphingolipid

Accumulation of DihydroceramidesSummary: Sphingosine kinase inhibitors are a new category of drugs that act on specific enzymes involved in sphingolipid metabolism to reduce the formation of a pro-cancer, pro-inflammatory lipid signaling molecule known as sphingosine-1 phosphate (S1P). Preclinical studies led by immunologist Christina Voelkel-Johnson, Ph.D., of the Medical University of South Carolina showed that a first-in-class sphingosine kinase 2 inhibitor slowed growth of aggressive prostate cancer cells.

A first-in-class sphingosine kinase 2 inhibitor slowed the growth of castration-resistant prostate cancer cells, in part by inhibiting the enzyme dihydroceramide desaturase (DEGS), but did not kill them, according to the results of preclinical in vitro and in vivo studies published in the December 2015 issue of Molecular Cancer Therapeutics by researchers at the Medical University of South Carolina (MUSC) and others.

Christina Voelkel-Johnson, Ph.D., Associate Professor of Microbiology and Immunology at MUSC, led the study, which was funded by a pilot grant from MUSC Hollings Cancer Center. Co-authors include Charles D. Smith, Ph.D., who developed the compound and led an earlier phase 1 trial at MUSC Hollings Cancer Center; oncologist Michael Lilly, M.D., a prostate cancer specialist; and Richard Drake, Ph.D., director of the Proteomics Core at MUSC, who has developed techniques to use MALDI imaging mass spectrometry to measure sphingolipid levels.

Sphingosine kinase inhibitors are a new category of drugs that reduce the generation of sphingosine-1-phosphate. This lipid signaling molecule promotes cancer cell growth and survival, thereby supporting the development of resistance to chemotherapy and radiation by cancer cells.

The study reported in Molecular Cancer Therapeutics showed that the compound YELIVA™ (ABC294640; RedHill Biopharma Ltd.; Tel Aviv, Israel) slowed prostate cancer cell proliferation by inhibiting sphingosine kinase 2, but also that it did something unexpected. “By inhibiting a second sphingolipid enzyme (DEGS), the compound increases levels of another class of lipids - dihydroceramides - which may contribute to the growth suppressive effects of the drug,” says Voelkel-Johnson. This study is the first to show activity for this compound against DEGS and to potentially link inhibition of DEGS to slowing the growth of castration-resistant prostate cancer cells. Treatment with YELIVA™ (ABC294640) increased dihydroceramide levels even in the absence of sphingosine kinase 2. 

The MUSC team conducted both in vitro and in vivo studies with YELIVA™ (ABC294640) in castration-resistant prostate cancer, relying on the MUSC Lipidomics Shared Resource for measurement of sphingolipid levels and the MUSC Proteomics Center for MALDI imaging mass spectrometry.

 In vitro studies conducted with castration-resistant mouse prostate cancer cells (TRAMP-C2) showed that treatment with YELIVA™ (ABC294640) reduced expression of the androgen receptor and the oncogene c-Myc, both important therapeutic targets for prostate cancer. Although many existing prostate cancer therapies target the androgen receptor, none directly target c-Myc.

To test in vivo response, one million TRAMP-C2 cells were injected under the skin of mice with an intact immune system, which were then treated with YELIVA™ (ABC294640) three days later. MALDI imaging mass spectrometry showed the presence of YELIVA™ (ABC294640) within murine tumors and confirmed in vitro findings of increased dihydroceramide levels.

“The significance of these findings is that this compound might be a novel therapeutic for advanced prostate cancer,” says Voelkel-Johnson, who believes that combination regimens of YELIVA™ (ABC294640) and focal radiation in this difficult-to-treat patient population deserve further study.

See full EurekAlert! release at http://www.eurekalert.org/pub_releases/2016-01/muos-anc012816.php

Image Caption:

The signal for ABC294640 is detected only when the drug but not the vehicle was administered (upper panel). The intensity for two different dihydroceramides is shown in the middle panel (dhC16-cer) and lower panel (dhC18-cer). A color bar indicates the signal intensity. Adapted with permission from the American Association for Cancer Research : Venant H, et al. The Sphingosine kinase 2 inhibitor ABC294640 reduces the growth of prostate cancer cells and results in accumulation of dihydroceramides In vitro and In vivo. Molecular Cancer Therapeutics; 2015 Dec; 14(12):2744-52. doi: 10.1158/1535-7163.MCT-15-0279.

fatty liver disease image 3

In results published on October 19, 2015 in the Journal of Lipid Research (http://dx.doi.org/10.1194/jlr.M063511), a team of translational scientists at the Medical University of South Carolina (MUSC) report a new reason why non-alcoholic steatohepatitis (NASH) worsens in people who are obese. The results may help prevent cirrhosis and liver cancer, according to co-senior authors Kenneth D. Chavin, M.D., Ph.D., a transplant surgeon in the MUSC Health Department of Surgery, and Lauren Ashley Cowart, Ph.D., Associate Professor in the Department of Biochemistry and Molecular Biology and Co-Director of the MUSC Center of Biomedical Research Excellence in Lipidomics and Pathobiology.

 NASH (also called non-alcoholic fatty liver disease) has become a major cause of liver disease requiring transplant. “In my 17 years of doing liver transplants, it’s gone from 4% of patients to around 20% of patients who get transplants because of NASH,” says Chavin. “In 10-15 years, because of advances with Hepatitis C, it will probably become the number one reason why patients get transplants.”

When excess dietary fats are consumed over time, fat deposits form in the liver and NASH can develop. Early-stage NASH is typically not associated with any physical symptoms; nearly 30% of people in the U.S. have it. Though obesity is correlated with the development of NASH, the team wanted to know exactly why NASH worsens to a stage requiring transplant in certain obese people. “Obesity doesn’t cause disease in every obese person and we don’t understand why it does in some but not others,” explains Cowart.

The team suspected that inflammation stemming from a lipid molecule called sphingosine-1-phosphate (S1P) might be responsible. They’d previously discovered in other organs that S1P is increased by excess dietary saturated fat.

Chavin took biopsies from human livers during transplant surgery and supplied them to Cowart, who determined the levels of sphingosine kinase 1, the enzyme that makes S1P. They found double the normal amount of sphingosine kinase 1 in livers of obese people with non-alcoholic steatohepatitis.

The team wanted more understanding of why S1P causes inflammation, but NASH has previously been difficult to mimic in the laboratory setting. They developed a new and highly improved preclinical model of NASH, wherein mice were fed on custom-designed diets of either high saturated fat or high unsaturated fat. Curiously, mice on each type of diet became obese, but only mice on the saturated fat diet developed inflammation and NASH-like pathology stemming from S1P. Taking the human and pre-clinical studies together, it’s likely that saturated fat, but not unsaturated fat, raises S1P levels in obese people, and it’s S1P that unleashes the inflammation that characterizes NASH.

Performing lipid studies in the laboratory is not easy—most biochemistry is water-based, and fat and water don’t easily mix. The group relied on the MUSC Sphingolipidomics Core laboratory, one of only a handful of such facilities in the country capable of developing the new methods needed to examine S1P for their study. Without lipidomics, we never would have understood that saturated fats activate this pathway,” says Cowart. The team is working to identify the S1P receptors responsible for inflammation in NASH, with the ultimate goal of designing treatments to prevent the need for a liver transplant in obese patients with NASH.

Does this work support the idea that it’s the type of fat, but not all fat, that leads to health problems? After all, mice fed a high unsaturated fat diet still became obese but were metabolically healthy. “Because the unsaturated fat diet didn’t cause NASH, it may provide a clue as to what actually links obesity to disease,” says Cowart. “Even if it’s difficult to lose weight, dietary modifications might prevent some disease associated with obesity.”

 MUSC researchers Tuoyu Geng, Ph.D., Alton Sutter, M.D.,Ph.D., Arun Palanisamy Ph.D., and Michael D. Harland also contributed to this study.

 This work was supported by a Veterans Affairs Merit Award, National Institutes of Health Grants 1R01HL117233 and 5P30GM103339-03 (L.A.C.), and National Institutes of Health Grant 1R01DK069369 to K.D.C .

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