Genotype-targeted local therapy of glioma

Abstract

Significance Lower-grade gliomas are often characterized by mutations in metabolism-related genes isocitrate dehydrogenase 1 ( IDH1 ) and IDH2 . Resection of these tumors is constrained by adjacent eloquent cortex, resulting in local failures. Studies showed that IDH mutant cells are sensitive to metabolic therapeutics, but these drugs are limited by systemic toxicities. We hypothesized that application of metabolism-altering therapeutics at the surgical margin would improve tumor control and minimize toxicity. We developed an intraoperative diagnostic assay to identify IDH mutations. We show that intratumoral administration of sustained release formulations of metabolism-altering compound prolongs survival in a mouse model of IDH mutant glioma. This genotype-based paradigm introduces a workflow in surgical oncology that can be extended to other tumors characterized by targetable molecular alterations.