Format

Send to

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

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

Author information

1
Beijing Neurosurgical Institute, Capital Medical University, 100050 Beijing, China.
2
Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Hong Kong, China; Center of Systems Biology and Human Health, The Hong Kong University of Science and Technology, Hong Kong, China.
3
Beijing Neurosurgical Institute, Capital Medical University, 100050 Beijing, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, 100050 Beijing, China.
4
Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China; Center of Systems Biology and Human Health, The Hong Kong University of Science and Technology, Hong Kong, China.
5
Beijing Neurosurgical Institute, Capital Medical University, 100050 Beijing, China; Department of Radio-therapy, Beijing Tiantan Hospital, Capital Medical University, 100050 Beijing, China.
6
Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China.
7
Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Hong Kong, China; Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China; Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong, China.
8
Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.
9
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, 100050 Beijing, China.
10
Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, 100050 Beijing, China.
11
Department of Radio-therapy, Beijing Tiantan Hospital, Capital Medical University, 100050 Beijing, China.
12
Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea; Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
13
Laboratory of Neuroscience and Brain Development, Beijing Key Laboratory of Gene Resource and Molecular Development, Beijing Normal University, 100875 Beijing, China. Electronic address: xfan@bnu.edu.cn.
14
Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Hong Kong, China; Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China; Center of Systems Biology and Human Health, The Hong Kong University of Science and Technology, Hong Kong, China. Electronic address: jgwang@ust.hk.
15
Beijing Neurosurgical Institute, Capital Medical University, 100050 Beijing, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, 100050 Beijing, China; Center of Brain Tumor, Beijing Institute for Brain Disorders, 100069 Beijing, China; China National Clinical Research Center for Neurological Diseases, 100050 Beijing, China. Electronic address: taojiang1964@163.com.

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

PMID:
30343896
DOI:
10.1016/j.cell.2018.09.038
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center