Lipidomics Research at MUSC
Paving the Way for New Anti-Cancer Compounds
Investigators at MUSC have begun to unravel the mystery of sphingolipids, named after the part-woman, part-lion sphinx who, in Greek mythology, devoured all those who could not answer her riddle. The metabolism of sphingolipids, a type of lipid found in cell membranes, particularly those of neurons, plays a key role in the complex mechanisms regulating cellular stress responses to environmental changes, and some metabolites, such as sphingosine 1 phosphate (S1P), have been implicated in cancer cell survival and the development of resistance to radiation and chemotherapy. Unraveling the mystery of sphingolipids could lead to a better understanding of the mechanisms underlying cancer cell proliferation and metastasis and could set the stage for a potent new group of anti-cancer compounds.
The Lipid Signaling in Cancer Program at Hollings Cancer Center, led by Besim Ogretmen, PhD, is exploring the role of novel lipid-mediated signaling pathways in oncogenesis and stress responses so that new anti-cancer therapies targeting these pathways can be developed. The Lipidomics Shared Resource (LSR), the leading component of the Lipid Signaling in Cancer Program, is directed by Alicja Bielawska, PhD, and funded in part by MUSC’s Center for Biomedical Research Excellence (COBRE) grant (Principal Investigator: Dr. Ogretmen) in Lipidomics and Pathobiology, now in its twelfth year. The LSR has analytical and synthetic units, providing medical institutions and pharmaceutical companies throughout the world with metabolic analyses of approximately 300 sphingolipid species and synthetic molecular tools to study sphingolipid metabolism.
A program project grant (PPG) application recently submitted by the Lipid Signaling in Cancer Program to the National Institutes of Health illustrates the scope of lipidomics cancer research at MUSC. The four investigators included in the PPG application plan to study sphingolipid signaling and metabolism in a wide variety of cancers, including head, neck, and lung (Dr. Ogretmen); liver (Charles Smith, PhD); prostate (James Norris, PhD); and colon (Christina Voelkel-Johnson, MS, PhD). Each investigator focuses on a different aspect of sphingolipid metabolism, with the common goal of identifying agents that can alter sphingolipid metabolism at crucial junctures. The LSR as well as an animal core (directed by Shikhar Mehrotra, PhD) and a biostatistics core (directed by Elizabeth Garrett-Mayer, PhD) provide the infrastructure necessary to help develop identified agents into new anti-cancer drugs.
Drs. Norris and Voelkel-Johnson are particularly interested in ceramides, which are thought to promote apoptosis (ie, programmed cell death). Levels of ceramides increase in response to stressors such as radiation therapy or chemotherapy. Acid ceramidase (AC), an enzyme that metabolizes ceramide to sphingosine, where it can be further metabolized into the prosurvival S1P, is also elevated in patients with prostate and other cancers who have developed resistance to radiotherapy. In a recent article (Journal of Clinical Investigation 2013;123:4344-4358), Dr. Norris, Dr. Bielawska, and other MUSC investigators showed that mice receiving radiation in conjunction with an AC inhibitor (LCL521) that was designed, developed, and patented by the LSR were far less likely to experience relapse and, when they did, experienced it much later than those receiving radiation alone. Dr. Norrisspeculatesthatthis striking effect may be attributed to the inhibitor’s efficacy against cancer stem cells. A spin-off biotechnology company (Sphingogene) is trying to raise money to take the AC inhibitors into clinical trials.
Dr. Smith, together with noted liver cancer investigator Melanie Thomas, M.D., is currently leading the first-in-human, first-in-class phase 1 trial of a sphingosine kinase (SK) inhibitor (ABC294640; Apogee Biotechnology Corporation, Hummelstown, PA), meant to block the phosphorylation of the proapoptotic sphingosine (encouraging cancer cell death) into the prosurvival S1P. In October 2013, Dr. Smith reported the interim findings of this phase 1 trial at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston. Thus far, the phase 1 trial has shown that ABC294640 can be administered safely to cancer patients at doses predicted to be therapeutic and that plasma sphingolipid levels can be quantified, providing useful pharmacodynamic information for this and other SK inhibitors.
Not only is MUSC conducting the trial of the first SK inhibitor in cancer patients, it is also one of a handful of centers chosen to conduct a phase 2 trial (Principal Investigator: Harry Drabkin, M.D.) of the antibody Asonep TM (Lpath, San Diego, CA). In contrast to the SK inhibitor ABC294640, which seeks to disrupt the conversion of sphingosine into S1P, Asonep directly binds the S1P molecule, leading to inhibition of tumor growth and lung metastasis, as was reported in a recent article jointly authored by Dr. Ogretmen’s group and Lpath (EMBO Mol Med 2012;4:761-75).
This world-class cadre of lipidomics investigators and the shared lipidomics core make MUSC an attractive site for clinical trials of agents targeting sphingolipid signaling and metabolism and position the institution to lead the way in translating this next generation of anti-cancer compounds into the clinic.