26 Poster Discussion - Poly(ADP-ribose) glycohydrolase inhibition sequesters NAD+ to potentiate the metabolic lethality of alkylating chemotherapy in IDH mutant tumor cells

Abstract

Background: Mutations in IDH1 or IDH2 characterize the most prevalent diffuse glioma of younger adulthood. DNA alkylator chemotherapy is an effective treatment for IDH mutant glioma, yet recurrences remain common and improved treatments are needed. Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor metabolite, serving as the currency of metabolic transactions critical for cell survival. IDH mutant cancer cells have unique dependencies on NAD+-dependent metabolic pathways, which include poly(ADP-ribose) polymerases (PARPs). PARPs catalyze oligomerization of NAD+ monomers into poly(ADP-ribose) (PAR) chains during cellular response to alkylating chemotherapeutics such as temozolomide (TMZ). We hypothesized that we could exploit the intrinsic metabolic vulnerability of IDH mutant cancer cells with combined treatment: TMZ would promote PARP activation and outflow consumption of cellular NAD+ pools, while concomitant inactivation of the PAR breakdown enzyme poly(ADP-ribose) glycohydrolase (PARG) would then sequester NAD+ as polymerized PAR, by blocking subsequent breakdown.