Pharmacodynamic Biomarker-Guided Metabolic Collapse of IDH-Mutant Glioma

This Idea award project evaluates a novel technique of microperfusion to sample the live extracellular glioma microenvironment. IDH-mutant gliomas are particularly vulnerable to NAMPT inhibitors, which help deplete tumor cells of NAD, a key metabolite for cellular function. We test three aims: 1) Can extracellular NAD provide a reflection of intracellular NAD, thereby discerning the intended effect of NAMPTi?; 2) what are the extracellular metabolic alterations that reflect relative sensitivity/resistance to NAMPTi?; 3) What are the candidate biomarkers of cytotoxicity? In the prior year, we established the bilateral murine microperfusion system in patient-derived glioma xenografts (PDXs), in addition to the analysis methods to assay the candidate metabolic biomarkers for each aim. This year, we evaluated the global metabolomic impacts of NAMPT inhibition on NAMPT sensitive or resistant IDH mutant or wild-type glioma xenografts viamicro perfusion. Findings to date suggest that the tumor-derived metabolic signature, with or without NAMPT inhibition, is strongly enriched for plasma-derived metabolites that resolves over time. Toward next years goals, we also performed pilot experiments to identify biomarkers of cytotoxicity using diphtheria toxin. The next year will be spent further evaluating the pharmacodynamic impact of NAMPT inhibition and cytotoxicity in these animal models, leveraging updated methods such as isotope tracing and microdialysis to deconvolute the tumor-specific metabolic signature from red blood cell-derived analytes.