In Situ Synthesis of Ceramides as a Cancer Therapeutic

Andrew Rudd
Appointment Period: 2017-2018, Grant Year: [32]

A defining factor of many cancers is a dysregulation of cell proliferation and apoptosis signaling pathways. Central to these signaling pathways are a class of sphingolipids called ceramides. These lipids have been identified as key regulators and executers of apoptosis, and defects in their metabolism are present in several cancers including glioblastoma, leukaemia, colon, ovarian and breast cancer. Because of their fundamental role in cancer progression and powerful tumor suppression capabilities, ceramides have gained attention as possible cancer therapeutics. Unfortunately, delivery of ceramides in vivo is limited by their poor cell permeability. Current therapeutic approaches utilize inhibitors of ceramide metabolism or more permeable short-chain ceramides to increase intracellular ceramide levels. The efficacy of these treatments can be hindered by the upregulated metabolic clearance of ceramide and the low apoptotic activity of short-chain ceramide derivatives compared to natural long-chain ceramides. Therefore, it would be beneficial to bypass the endogenous lipid metabolism and exogenously deliver long-chain ceramides to tumor cells.

We propose a new class of cancer therapeutics in which proapoptotic ceramides are assembled selectively within tumor cells through the chemoselective ligation of cell permeable precursors. We plan to leverage a novel lipid ligation technique developed in our lab, termed traceless ceramide ligation (TCL), to chemoselectively ligate ceramide precursors within cancer cells (fig. 1A). Using this method, we have successfully assembled specific ceramides within cancer cells at concentrations which trigger apoptosis. Additionally, by utilizing a photocaged ceramide precursor, we can photoinitiate cell death in cultured cancer cells with cellular resolution. We plan to further develop this technology for the selective delivery of proapoptotic ceramides to cancer cells. By incorporating cancer targeting elements such as folic acid and/or Near IR compatible photocages into our ceramide forming precursors, we will direct their accumulation and ligation within cancerous cells (fig. 1B). We hope that by increasing cellular ceramide levels and directly activating the intrinsic apoptosis pathway, we can offer a new paradigm of cancer therapeutics.

PUBLICATIONS (resulting from this training)

Brea RJ, Rudd AK, Devaraj NK. Non-Enzymatic Biomimetic Remodeling of Phospholipids in Synthetic Liposomes. (2016) Proc. Natl. Acad. Sci. USA 113 (31), 8589-8594. PMID: 27439858 PMCID: PMC4978229

Rudd AK, Cuevas JM, Devaraj NK. SNAP-tag Reactive Lipid Anchors Enable Targeted and Spatiotemporally Controlled Localization of Proteins to Phospholipid Membranes. (2015) J. Am. Chem. Soc. 137(15), 4884-4887. PMID: 25830488