Research ArticleGlioblastoma

Targeting pyrimidine synthesis accentuates molecular therapy response in glioblastoma stem cells

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Science Translational Medicine  07 Aug 2019:
Vol. 11, Issue 504, eaau4972
DOI: 10.1126/scitranslmed.aau4972

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Targeting metabolic changes in glioblastoma

Glioblastoma (GBM) is the most aggressive brain cancer in adults. GBM stem cells (GSCs) contribute to tumor initiation and therapeutic resistance. Understanding the metabolic alterations in GSCs could help the development of new therapeutic strategies. Now, Wang et al. revealed that pyrimidine biosynthesis is up-regulated in GSCs and correlated with tumor grade in patients with GBM. This metabolic alteration was necessary for GSC maintenance, and combined targeting of pyrimidine synthesis and tumor-specific driver mutations using approved drugs improved survival and inhibited tumor growth compared to the single treatments in mouse models. Targeting metabolic reprogramming in combination with mutation-specific therapies might improve clinical outcome in patients with GBM.

Abstract

Glioblastoma stem cells (GSCs) reprogram glucose metabolism by hijacking high-affinity glucose uptake to survive in a nutritionally dynamic microenvironment. Here, we trace metabolic aberrations in GSCs to link core genetic mutations in glioblastoma to dependency on de novo pyrimidine synthesis. Targeting the pyrimidine synthetic rate-limiting step enzyme carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, dihydroorotase (CAD) or the critical downstream enzyme dihydroorotate dehydrogenase (DHODH) inhibited GSC survival, self-renewal, and in vivo tumor initiation through the depletion of the pyrimidine nucleotide supply in rodent models. Mutations in EGFR or PTEN generated distinct CAD phosphorylation patterns to activate carbon influx through pyrimidine synthesis. Simultaneous abrogation of tumor-specific driver mutations and DHODH activity with clinically approved inhibitors demonstrated sustained inhibition of metabolic activity of pyrimidine synthesis and GSC tumorigenic capacity in vitro. Higher expression of pyrimidine synthesis genes portends poor prognosis of patients with glioblastoma. Collectively, our results demonstrate a therapeutic approach of precision medicine through targeting the nexus between driver mutations and metabolic reprogramming in cancer stem cells.

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