A phase 1 trial at MUSC Hollings Cancer Center of a first-in-kind sphingosine kinase (SK) 2 inhibitor (YELIVATM, RedHill Biopharma Ltd, Israel) showed it to be safe and well-tolerated by patients with solid tumors, report MUSC investigators in the August 2017 issue of Clinical Cancer Research.
Led by Carolyn D. Britten, M.D., associate director for clinical investigations at the MUSC Hollings Cancer Center, the trial also established a recommended dose for the SK2 inhibitor and showed that it lowers plasma levels of sphingosine 1 phosphate (S1P) in patients with solid organ tumors.
“Sphingolipid metabolism has been widely studied in cancer models, but translation of these basic science results to the clinic is limited,” says Britten. “The phase 1 trial was unique because it provided the first data on sphingolipid profiles in patients treated with an SK inhibitor.”
Sphingolipids are a class of lipids known to be involved in the growth of solid tumor cancers. S1P, formed when sphingosine picks up a phosphate group from SK1 or SK2 enzymes, has been shown to promote the proliferation of cancer cells and the development of treatment resistance.
By blocking the activity of SK2, the inhibitor helps prevent the formation of S1P. The SK2 inhibitor was developed by Charles D. Smith, Ph.D., formerly a professor at MUSC, and was later licensed to RedHill Biopharma. Smith is currently on faculty at Penn State University and is a co-author of the Clinical Cancer Research article.
Britten is also the principal investigator of a phase 2 trial of the SK2 inhibitor as a second-line monotherapy in patients with advanced hepatocellular carcinoma (HCC) who have experienced tumor progression despite treatment with currently available FDA-approved therapies. The most common primary malignant cancer of the liver, HCC also has one of the highest mortality rates among cancers. The phase 2 trial is now open and recruiting patients at Hollings, with an initial goal of enrolling 12 patients. If a response is seen in these patients, additional patients will be recruited, with a target enrollment of 39.
The study is being funded by a grant from the National Cancer Institute (NCI) awarded in 2016 to Hollings, an NCI-designated cancer center, with additional support from RedHill. Besim Ogretmen, Ph.D., Endowed Chair in Lipidomics & Drug Discovery in the SmartState® Center for Lipidomics, Pathobiology and Therapy and professor of Biochemistry & Molecular Biology at MUSC, is the principal investigator for the $8.9 million NCI Program Project Grant (PPG), which funds a total of three projects and four shared resources. The collective aim of this PPG is to foster collaboration across clinical and laboratory research for the study of signaling in sphingolipids for cancer therapeutics.
“It is gratifying to see that Hollings is becoming a center for clinical trials of sphingolipid-related therapeutics,” says Ogretmen.
Other trials with the selective SK2 inhibitor are underway to assess its efficacy in a wide range of advanced tumors that are not responsive to standard treatments.