Steroid-dependent metabolic rewiring reveals novel therapeutic and imaging approaches for glioblastoma.

Abstract

Steroid anti-inflammatory drugs, such as dexamethasone, are routinely used to manage brain tumor-associated edema, yet their impact on brain tumor metabolism remains understudied. Here, a metabolomic screen in naïve glioblastoma cells treated with dexamethasone revealed the accumulation of <i>N</i>¹-methylnicotinamide, a nicotinamide <i>N</i>-methyltransferase (NNMT) product, through glucocorticoid receptor activation. Using stable isotope-assisted metabolomics in patients with glioblastoma, we showed that nicotinamide conversion into <i>N</i>¹-methylnicotinamide exceeds that into NAD⁺, leading to a ~7-fold accumulation of <i>N</i>¹-methylnicotinamide in tumor compared to surrounding brain tissue. In orthotopic models, NNMT activity was enhanced by dexamethasone selectively in glioblastoma tumors but not in contralateral brain. Leveraging the tumor-specific activity of NNMT, we developed a novel ¹¹C-nicotinamide-based positron emission tomography (PET) approach to visualizing glioblastoma tumors. Furthermore, our findings demonstrate that the dexamethasone-induced methionine-dependent nicotinamide methylation becomes detrimental for glioblastoma when combined with a methionine-restricted diet. These results show that steroids rewire methionine and nicotinamide metabolism, enabling the development of innovative PET imaging and metabolic therapies for glioblastoma.