18IN - Glioma and IDH targeting

Date 06 March 2018
Event TAT 2018 - Targeted Anticancer Therapies
Session Metabolic targets
Topics Anti-Cancer Agents & Biologic Therapy
Central Nervous System Malignancies
Presenter Daniel Cahill
Citation Annals of Oncology (2018) 29 (suppl_3): iii1-iii6. 10.1093/annonc/mdy046
Authors D. Cahill
  • -, Massachusetts General Hospital, 2114 - Boston/US

Abstract

Approximately 80% of WHO grade II and III gliomas, and secondary glioblastomas (representing 25% of adult diffuse gliomas overall) harbor mutations in the metabolic isocitrate dehydrogenase enzymes encoded by the IDH1/2 genes. These mutations, now recognized as the genetic hallmark of these cancers, result in neomorphic enzymatic activity driving overproduction of the oncometabolite 2-hydroxyglutarate (2-HG), which leads to profound reprogramming of tumor cellular metabolism. As a result, IDH1-mutant gliomas are dependent upon the canonical coenzyme NAD+ for survival. It is known that poly(ADP-ribose) polymerase (PARP) activation consumes NAD+ during base excision repair of chemotherapy-induced DNA damage. We therefore hypothesized that a strategy combining NAD+ biosynthesis inhibitors with the alkylating chemotherapeutic agent temozolomide could potentiate NAD+ depletion-mediated cytotoxicity in mutant IDH1 cancer cells.