Acid Ceramidase Inhibitors: A De Novo Drug Target and a New Class of Drug for Glioblastoma

Glioblastoma remains the most common malignant cancer of the central nervous system with an overall survival <1.5 years. Therapeutically resistant glioblastoma or glioblastoma stem-like cells (GSC) are hypothesized to cause inevitable recurrence. Proteomic analysis of 601 glioblastoma-specific proteins revealed, for the first time, that the expression of acid ceramidase (ASAH1) is associated with poor survival. CD133+ GSC express significantly higher ASAH1 compared to CD133- GSC and glioblastoma cell line U87MG, providing a target for a therapy tailored toward GSCs. Strikingly, U87MG cells and 3 different patient-derived glioblastoma stem-like cancer cell lines were efficiently killed, through apoptosis, by three different known ASAH1 inhibitors with IC50’s ranging 11-104mM, while temozolomide, the only FDA-approved oral chemotherapy for GBM, had minimal GSC-targeted effects. Carmofur is an ASAH1 inhibitor that crosses the blood-brain barrier, and has been approved in Japan since 1981 for colorectal cancer therapy, poising for repurposing and translation to glioblastoma clinical trials.