Mutational landscape of secondary glioblastoma guides MET-targeted trial in brain tumor
Authors: Huimin Hu, Quanhua Mu, Zhaoshi Bao, Yiyun Chen, Yanwei Liu, Jing Chen, Kuanyu Wang, Zheng Wang, Yoonhee Nam, Biaobin Jiang, Jason K. Sa, Hee-Jin Cho, Nam-Gu Her, Chuanbao Zhang, Zheng Zhao, Ying Zhang, Fan Zeng, Fan Wu, Xun Kang, Yuqing Liu, Zenghui Qian, Zhiliang Wang, Ruoyu Huang, Qiangwei Wang, Wei Zhang, Xiaoguang Qiu, Wenbin Li, Do-Hyun Nam, Xiaolong Fan, Jiguang Wang, Tao Jiang
Summary:
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.
Source: Cell, 2018
Summary:
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.
Source: Cell, 2018