Mutational Landscape of Secondary Glioblastoma Guides MET-Targeted Trial in Brain Tumor

Cell. 2018 Nov 29;175(6):1665-1678.e18. doi: 10.1016/j.cell.2018.09.038. Epub 2018 Oct 18.

Abstract

Low-grade gliomas almost invariably progress into secondary glioblastoma (sGBM) with limited therapeutic option and poorly understood mechanism. By studying the mutational landscape of 188 sGBMs, we find significant enrichment of TP53 mutations, somatic hypermutation, MET-exon-14-skipping (METex14), PTPRZ1-MET (ZM) fusions, and MET amplification. Strikingly, METex14 frequently co-occurs with ZM fusion and is present in ∼14% of cases with significantly worse prognosis. Subsequent studies show that METex14 promotes glioma progression by prolonging MET activity. Furthermore, we describe a MET kinase inhibitor, PLB-1001, that demonstrates remarkable potency in selectively inhibiting MET-altered tumor cells in preclinical models. Importantly, this compound also shows blood-brain barrier permeability and is subsequently applied in a phase I clinical trial that enrolls MET-altered chemo-resistant glioma patients. Encouragingly, PLB-1001 achieves partial response in at least two advanced sGBM patients with rarely significant side effects, underscoring the clinical potential for precisely treating gliomas using this therapy.

Trial registration: ClinicalTrials.gov NCT02978261.

Keywords: MET tyrosine-kinase inhibitor; PLB-1001; cancer genomics; clinical trial; data science; precision neuro-oncology; secondary glioblastomas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / metabolism
  • Blood-Brain Barrier / pathology
  • Brain Neoplasms* / drug therapy
  • Brain Neoplasms* / genetics
  • Brain Neoplasms* / metabolism
  • Brain Neoplasms* / pathology
  • Drug Delivery Systems
  • Exons*
  • Female
  • Glioblastoma* / drug therapy
  • Glioblastoma* / genetics
  • Glioblastoma* / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mutation*
  • Protein Kinase Inhibitors* / pharmacokinetics
  • Protein Kinase Inhibitors* / pharmacology
  • Proto-Oncogene Proteins c-met* / antagonists & inhibitors
  • Proto-Oncogene Proteins c-met* / genetics
  • Proto-Oncogene Proteins c-met* / metabolism
  • Rats, Sprague-Dawley
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Protein Kinase Inhibitors
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • MET protein, human
  • Proto-Oncogene Proteins c-met

Associated data

  • ClinicalTrials.gov/NCT02978261