Glioma intelligence from behind enemy lines

Glioma intelligence from behind enemy lines Molecularly diverse gliomas may leverage convergent metabolic survival pathways that can be therapeutically targetable. Microdialysis enables sampling of the extracellular microenvironment and represents a previously underutilized opportunity to characterize and pharmacodynamically monitor living human gliomas, in situ. Our preliminary data from intraoperatively acquired glioma microdialysate reveal strong enrichment for methionine-associated pathways of cancer resiliency, including polyamine synthesis. Specifically, results to date have identified guanidinoacetate (GAA) as the most highly upregulated metabolite in glioma microdialysate, which we hypothesize results from upregulated polyamine synthesis within the tumor. This study will determine the reproducibility and potential therapeutic implications of our findings across a larger cohort of gliomas, asking if microdialysis could be leveraged to obtain mechanistic feedback during early phase clinical evaluation of candidate therapies. To interrogate methionine metabolism human gliomas in situ, we will perform intra-operative microdialysis and methionine tracing, comparing the metabolome of microdialysate and tissue from tumor and adjacent brain. Resected tissue will be used to determine the cellular source of methionine-associated metabolites. Recent studies have demonstrated that diverse tumors can escape DMFO-mediated polyamine metabolism by upregulation of polyamine transporters. Dual blockade of polyamine synthesis and polyamine transports with DMFO+AMXT 1501 has been shown to improve outcomes in preclinical models. To mechanistically interrogate polyamine metabolism we will perform a combination of preclinical and clinical studies leveraging microdialysis. In a phase 0 study, patients will be randomized to vehicle, DMFO, or DMFO+AMXT 1501, prior to dual administration of DMFO+AMXT to determine the extracellular pharmacodynamic changes induced by early therapeutic stress. Collectively, these studies will test how microdialysis can be used to perform biochemical reconnaissance within the live human glioma, with and without therapeutic challenge, to gain “glioma intelligence from behind enemy lines.”