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

Huimin Hu1, Quanhua Mu2, Zhaoshi Bao3

  • 1Beijing Neurosurgical Institute, Capital Medical University, 100050 Beijing, China.

Cell
|October 23, 2018
PubMed

Insights

Researchers identified key genetic alterations, including MET-exon-14-skipping, in secondary glioblastoma (sGBM). A novel drug, PLB-1001, shows promise in treating these MET-altered gliomas, offering new therapeutic avenues.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Low-grade gliomas frequently transform into secondary glioblastomas (sGBM), a process with limited treatment options and unclear mechanisms.
  • Understanding the genetic drivers of sGBM is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the mutational landscape of secondary glioblastoma.
  • To identify novel therapeutic targets and agents for sGBM treatment.

Main Methods:

  • Analysis of the mutational landscape in 188 sGBM samples.
  • Preclinical studies of MET-exon-14-skipping (METex14) and PTPRZ1-MET (ZM) fusions.
  • Evaluation of the MET kinase inhibitor PLB-1001 in preclinical models and a Phase I clinical trial.

Main Results:

  • Significant enrichment of TP53 mutations, somatic hypermutation, METex14, ZM fusions, and MET amplification was observed.
  • METex14, often co-occurring with ZM fusion, was found in approximately 14% of cases and associated with a worse prognosis.
  • PLB-1001 demonstrated potent inhibition of MET-altered glioma cells, crossed the blood-brain barrier, and showed efficacy in a Phase I trial for chemo-resistant gliomas.

Conclusions:

  • MET alterations, particularly METex14, are significant drivers in sGBM progression.
  • PLB-1001 represents a promising targeted therapy for MET-altered gliomas, including chemo-resistant cases.
  • Precision medicine approaches targeting specific genetic alterations hold potential for improving glioma treatment outcomes.
Keywords:
MET tyrosine-kinase inhibitorPLB-1001cancer genomicsclinical trialdata scienceprecision neuro-oncologysecondary glioblastomas

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