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 Molecular Cancer Therapeutics.
Sphingosine kinase inhibitors are a new category of drugs that reduce the generation of sphingosine-1-phosphate.
This lipid signalling 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 ABC294640 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,” said Christina Voelkel-Johnson, Ph.D., Associate Professor of Microbiology and Immunology at Medical University of South Carolina (MUSC), who led the study.
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 ABC294640 increased dihydroceramide levels even in the absence of sphingosine kinase 2.
The MUSC team conducted both in vitro and in vivo studies with 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 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 ABC294640 three days later.
MALDI imaging mass spectrometry showed the presence of ABC294640 within murine tumours 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 ABC294640 and focal radiation in this difficult-to-treat patient population deserve further study.
[hr] Source: The Medical University of South Carolina