Mapping the genomic landscape of secondary glioblastoma (sGBM) identifies MET as a therapeutic target.
Major finding: Mapping the genomic landscape of secondary glioblastoma (sGBM) identifies MET as a therapeutic target.
Concept: PLB-1001 is a selective blood–brain barrier–permeable MET inhibitor with activity against MET-altered sGBM.
Impact: PLB-1001 achieves responses in MET-altered glioma, supporting its further clinical investigation.
Low-grade gliomas generally progress into secondary glioblastomas (sGBM). Treatment options are limited, and sGBMs typically recur after standard therapy. To identify potential therapeutic targets, Hu, Mu, Bao, and colleagues characterized the genomic landscape of sGBM via integrated genomic and transcriptomic analysis of 188 sGBM samples from patients. This analysis revealed enrichment of mutations in TP53, somatic hypermutation, MET–exon-14 skipping (METex14), PTPRZ1–MET fusions, and MET amplifications. METex14 was present in 11 of 78 (14%) patients with RNA-sequencing data, resulted in hyperactivation of MET signaling, and was associated with poor patient survival. Further, co-occurrence of METex14 and PTPRZ1–MET resulted in increased recruitment of tumor-associated macrophages, altering the tumor microenvironment to promote glioma progression. These findings suggest the potential for therapeutic targeting of MET in sGBM, and previously developed MET inhibitors had activity against glioma cells harboring METex14 and PTPRZ1–MET in vitro. Molecular dynamics simulation characterized the highly selective ATP-competitive small-molecule MET inhibitor PLB-1001, which occupied the ATP-binding pocket. PLB-1001 exhibited better blood–brain barrier penetrance than other MET inhibitors and inhibited MET signaling to suppress the growth of MET-altered glioma xenografts and orthotopic tumors. Based on these findings, PLB-1001 was evaluated in an open-label phase I dose-escalation study of 18 patients with recurrent high-grade gliomas with METex14 and/or PTPRZ1–MET, 9 patients with sGBM, and 9 patients with grade III glioma. PLB-1001 had an acceptable safety profile and achieved partial responses in two patients with sGBM, with a median duration of response of 62.5 days. Collectively, these findings indicate that MET may be an effective therapeutic target in patients with sGBM, and support further investigation of PLB-1001 in patients with MET-altered tumors.
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