Dr. Cabot, a respected lipid biochemist and cell biologist, has published extensively on the development and reversal of multidrug resistance in cancer. His investigations of tumor resistance to chemotherapy were acknowledged with the American Cancer Society’s Science Writer’s Award, in 1999. Cabot is also credited with crucial work on pivotal second messengers that transfer and amplify chemical signals for events within neoplastic cells. He serves on numerous review panels including those of the National Cancer Institute, Department of Defense Breast Cancer Research Program, and the United States –Israel Binational Science Foundation. He collaborates with groups at the University of Virginia Cancer Center, Charlottesville, Penn State/Hershey College of Medicine, Georgia Institute of Technology, University of The Basque Country, Bilbao, Spain, and the Institute for Advanced Chemistry of Catalunya, Barcelona, Spain, on issues related to drug discovery and cancer therapy.
Over the last decade, in collaboration with physicians and scientists at Los Angeles Children’s Hospital and Texas Tech University, Lubbock, Cabot helped develop use of a Vitamin A analog, called 4-HPR also known as fenretinide, which is being evaluated in Phase I/II clinical trials (solid tumors, leukemias, lymphomas) as a single agent or in combination with partnering compounds that magnify anticancer activity. Although administered as an IV emulsion, fenretinide has also been developed in “cookie dough”- by mouth formulation and is being evaluated in trials for treatment of pediatric neuroblastoma. Use of fenretinide is showing promise for selectively killing certain types of cancer cells. The agent works by stimulating overproduction of normal cellular waxes, known as ceramides, that when produced in excess, are lethal to cancer cells.
Research in Dr. Cabot’s laboratory focuses on sphingolipid metabolism as it relates to cancer growth and therapy. Sphingolipid metabolism is an area of cancer research that has risen to clinical prominence over the last 15 years. This is because ceramide, the aliphatic backbone of sphingolipids, acts as a powerful tumor suppressor, whereas its glycosylated product, glucosylceramide, catalyzed by the enzyme glucosylceramide synthase, is anti-apoptotic and a biomarker of multidrug resistance, as identified by Cabot in the mid-1990’s. Acid ceramidase, another important sphingolipid enzyme regulator of cancer cell growth, has recently been identified as candidate gene for development of new cancer diagnostics and touted as a therapeutic target in metastatic cancer. Like glucosylceramide synthase, acid ceramidase dampens the tumor suppressor properties of ceramide via ceramide hydrolysis and leads to the generation of sphingosine 1-phosphate, a powerful cancer cell mitogen. Thus, sphingolipid metabolism is a dynamic process with complex orchestration, impact, and clinical applications. Importantly, these enzymes are druggable targets.
Although many anti-cancer agents are themselves ceramide generators, this benefit can be outweighed by a cancer cell’s capacity to metabolize ceramide, a defense or form of “drug resistance” employed to detoxify the tumor suppressor effects of this sphingolipid. In an effort to circumvent this ceramide resistance pathway, Cabot, in his studies of various partnering agents, has discovered that tamoxifen, the gold standard anti-estrogen used in treatment of ER+ breast cancer, inhibits ceramide glycosylation and ceramide hydrolysis, the major metabolic pathways used by cancer cells to limit ceramide’s apn>optotic impact. In addition, in place of using ceramide-generating agents (such as 4-HPR), the group has been exploring administration of cell-permeable, short-chain ceramides, in nanoliposomal formulations, a collaborative effort between ECU, UVA Charlottesville, and Penn State Hershey Cancer Center. The employ of nanotechnology improves short-chain ceramide delivery and potency, and when partnered with tamoxifen (or similar efficacy enhancers), the effects as tested across tumor types, are powerfully synergistic. The brunt of research in the laboratory is directed toward fine-tuning use of short-chain nanoformulated ceramides for treatment of various neoplasms. Cabot believes that “partnering agents” are a key to augmenting ceramide efficacy and affirms that rationally designed combinatorial therapies have the potential to achieve synergistic treatment of cancer. This is a promising new area of targeted cancer therapeutics, as ceramide is cytotoxic to cancer cells but minimally toxic to normal cells of the body.
Work is supported by a Program Project Grant from the NIH/ National Cancer Institute.
Morad SA, Levin JC, Tan SF, Fox TE, Feith DJ, Cabot MC. Novel off-target effect of tamoxifen--inhibition of acid ceramidase activity in cancer cells. Biochim Biophys Acta. 2013
Morad SA, Madigan JP, Levin JC, Abdelmageed N, Karimi R, Rosenberg DW, Kester M, Shanmugavelandy SS, Cabot MC. Tamoxifen magnifies therapeutic impact of ceramide in human colorectal cancer cells independent of p53. Biochem Pharmacol. 2013
Morad SA, Messner MC, Levin JC, Abdelmageed N, Park H, Merrill AH Jr, Cabot MC. Potential role of acid ceramidase in conversion of cytostatic to cytotoxic end-point in pancreatic cancer cells. Cancer Chemother Pharmacol. 2013
Morad SA, Cabot MC. Ceramide-orchestrated signalling in cancer cells. Nat Rev Cancer. 2013
Morad SA, Levin JC, Shanmugavelandy SS, Kester M, Fabrias G, Bedia C, Cabot MC. Ceramide--antiestrogen nanoliposomal combinations--novel impact of hormonal therapy in hormone-insensitive breast cancer. Mol Cancer Ther. 2012
Senchenkov A, Han TY, Wang H, Frankel AE, Kottke TJ, Kaufmann SH, Cabot MC.Enhanced ceramide generation and induction of apoptosis in human leukemia cells exposed to DT(388)-granulocyte-macrophage colony-stimulating factor (GM-CSF), a truncated diphtheria toxin fused to human GM-CSF. Blood. 2001
Liu YY, Han TY, Giuliano AE, Cabot MC. Ceramide glycosylation potentiates cellular multidrug resistance. FASEB J. 2001
Senchenkov A, Litvak DA, Cabot MC. Targeting ceramide metabolism--a strategy for overcoming drug resistance. J Natl Cancer Inst. 2001