PP61. THE ROLE OF NICOTINAMIDE METABOLISM IN CHEMOSENSITIVITY IN GLIOBLASTOMA MULTIFORME

Abstract

Glioblastoma multiforme (GBM) is a highly aggressive grade IV glial cancer that shows a high degree of intra tumour heterogeneity, with a median survival time of only 18 months. The standard of care is surgical resection followed by combined radiation and chemotherapy in the form of the alkylating agent temozolomide (TMZ). However, tumour recurrence is common with acquired resistance to both TMZ and radiation. Novel drug combinations are desperately required to improve outcomes for patients with this devastating form of cancer. Targeting tumour metabolism is a promising strategy. Ecto-5'-nucleotidase (NT5E) is a metabolic enzyme bound to the extracellular membrane. Although its primary role is involved in nucleotide metabolism, where it catalyses the removal of phosphate groups from nucleoside monophosphates, it has been implicated as playing a significant role in the development and progression of cancer. Recent studies have highlighted its role in the salvage of extracellular nicotinamide metabolites, enabling cells to fuel NAD dependent reactions. In addition, data from the TCGA database shows that the expression of enzymes involved in nicotinamide metabolism, including NT5E, NAMPT and NNMT, are predictive of survival in patients with GBM. Results from our in vitro studies indicate that pharmacological inhibition (using APCP) or knockdown of NT5E sensitises GBM cells to the NAD depleting agent FK866 and to TMZ as assessed by a reduction in proliferation. Moreover, NT5E null cells exhibit increased activation of apoptosis and a greater degree of cell death in the presence of TMZ and FK866, and the drugs in combination show enhanced effects. Furthermore, treatment of GBM cells with FK866 significantly reduces intracellular NAD and NADH levels. This depletion of NAD could result in a reduced glycolytic capacity, loss of efficient DNA repair mechanisms mediated via the PARP family, and disruption to the cell cycle through loss of normal sirtuin activity. FK866 has already been shown to have a clear, safe toxicity profile in clinical trials of other cancers and importantly it is predicted to cross the blood brain barrier. The combined use of FK866 and TMZ is a strategy that could be explored to combat GBM recurrence and improve patient survival, stratified on NT5E status.