Editors' ChoiceCancer

Three hits, one drug

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Science Signaling  07 Apr 2020:
Vol. 13, Issue 626, eabc0532
DOI: 10.1126/scisignal.abc0532

A pediatric brain cancer often caused by coincident mutations might be treated with a fungal analog.

Pediatric gliomas are notoriously aggressive, and patients with the diffuse intrinsic pontine glioma (DIPG) subtype have no effective treatment options. To identify potential therapeutic targets, Fortin et al. generated mouse models expressing common mutations that often co-occur during early tumor development and appear to be selective for tumor progression. Knockin mice expressing mutant bone morphogenetic protein (BMP) type I receptor (ACVR1G328V) in neural progenitor cells did not develop tumors. However, mice exhibited neurological symptoms and a greater number of oligodendroglial cells than their wild-type littermates. Analyses of primary glial cells ex vivo revealed that ACVR1G328V increased the expression of platelet-derived growth factor receptor (PDGFRA) and activated transcription factors that decreased oligodendroglial cell differentiation and increased their proliferation. Introducing a mutation in histone H3 (HIST1H3BK27M) had a cooperative effect on these phenotypes but still did not generate tumors. Adding a third coincident mutation, in the catalytic subunit of phosphoinositide-3-kinase (PIK3CAH1047R), conserved these phenotypes and induced the development of lethal, high-grade diffuse gliomas. To find a potential therapeutic, the authors started with E6201, a synthetic analog of a natural product of a fungus and an inhibitor of mitogen-activated protein kinase (MAPK) pathway kinases induced by PDGFRA. Unexpectedly, the authors found that E6201 also bound to and inhibited ACVR1 and, consequently, reduced the viability of DIPG-derived cell lines in culture. Peripheral administration of E6201 prolonged the survival of xenografted mice, suggesting it might also be therapeutic in patients. E6201 is in clinical trials for brain-metastatic melanoma and penetrates the blood-brain barrier; if tolerated well, the drug might be explored for use in pediatric patients with DIPG.

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