The growth of castration-resistant prostate cancer cells was reduced by a first-in-class sphingosine kinase 2 inhibitor, but the cells were not killed. These data, from cell and mouse models, were published in Molecular Cancer Therapeutics.1
This study looked at a drug, ABC294640 (YELIVA; RedHill Biopharma Ltd; Tel Aviv, Israel), that inhibits sphingosine kinase, the enzyme that produces sphingosine-1-phosphate. Sphingosine-1-phosphate is a lipid signaling molecule that promotes cancer cell growth and survival. The intent of this drug is to reduce the development of resistance to chemotherapy and radiation by cancer cells.
ABC294640 inhibited sphingosine kinase 2 and thus slowed prostate cancer cell proliferation, and it also 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, PhD, associate professor of Microbiology and Immunology at the Medical University of South Carolina in Charleston.
This study is the first to find that ABC294640 has activity against DEGS and that inhibiting DEGS may be linked to slowing the growth of castration-resistant prostate cancer cells. Dihydroceramide levels increased after treatment with ABC294640, even when sphingosine kinase 2 was absent.
Castration-resistant prostate cancer cells from mice that were treated with ABC294640 had reduced expression of 2 important targets in prostate cancer: the androgen receptor and the oncogene c-Myc. No existing therapies target c-Myc, though many target the androgen receptor.
Mice injected with castration-resistant prostate cancer cells and treated with ABC294640 showed increased dihydroceramide levels. Furthermore, ABC294640 was present in the tumors.
“The significance of these findings is that this compound might be a novel therapeutic for advanced prostate cancer,” said Voelkel-Johnson. She believes that combination regimens of ABC294640 and focal radiation in this difficult-to-treat patient population deserve further study.
1. Venant H, Rahmaniyan M, Jones EE, 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. Mol Cancer Ther. 2015;14:2744. doi:10.1158/1535-7163.MCT-15-0279.