@article{f3c19815cb2744bf8e419093283a364d,
title = "Mutational Landscape of Secondary Glioblastoma Guides MET-Targeted Trial in Brain Tumor",
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.",
keywords = "MET tyrosine-kinase inhibitor, PLB-1001, cancer genomics, clinical trial, data science, precision neuro-oncology, secondary glioblastomas",
author = "Huimin Hu and Quanhua Mu and Zhaoshi Bao and Yiyun Chen and Yanwei Liu and Jing Chen and Kuanyu Wang and Zheng Wang and Yoonhee Nam and Biaobin Jiang and Sa, {Jason K.} and Cho, {Hee Jin} and Her, {Nam Gu} and Chuanbao Zhang and Zheng Zhao and Ying Zhang and Fan Zeng and Fan Wu and Xun Kang and Yuqing Liu and Zenghui Qian and Zhiliang Wang and Ruoyu Huang and Qiangwei Wang and Wei Zhang and Xiaoguang Qiu and Wenbin Li and Nam, {Do Hyun} and Xiaolong Fan and Jiguang Wang and Tao Jiang",
note = "Funding Information: This work is a pilot study from the Chinese Glioma Genome Atlas (CGGA) and Asian Glioma Genome Atlas (AGGA) Research Networks. The authors would like to especially thank all contributors to CGGA and AGGA. The authors thank Dr. Fei Sun from HKUST for helpful comments and acknowledge TCGA research network, Gregory M. Kiez and Mehmet Kutman Foundation, and the Yale University Department of Neurosurgery for providing access to sequencing data. This work was supported by grants from National Key Research and Development Plan ( 2016YFC0902500 ); Natural Science Foundation of China (NSFC)/ Research Grants Council (RGC) , Hong Kong, China Joint Research Scheme (81761168038 to T.J. and N_HKUST606/17 to J.W.); National Natural Science Foundation of China ( 81502495 , 81502606 , and 81702460 ); Capital Foundation of Medical Developments ( 2016-1-1072 ); Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support ( ZYLX201708 ); Beijing Nova Program ( Z171100001117022 ); and Beijing Administration of Hospitals{\textquoteright} Youth Program ( QML20160502 ). J.W. was also supported by Collaborative Research Fund (CRF) , Hong Kong ( C6002-17GF ); Hong Kong Epigenomics Project ( LKCCFL18SC01-E ); and HKUST start-up and initiation grants and received substantial support from BDBI Lab . D.-H.N. was supported by the grant of Korea Health Technology R&D project through KHIDI funded by the Ministry of Health & Welfare, Republic of Korea ( HI14C3418 ). Funding Information: This work is a pilot study from the Chinese Glioma Genome Atlas (CGGA) and Asian Glioma Genome Atlas (AGGA) Research Networks. The authors would like to especially thank all contributors to CGGA and AGGA. The authors thank Dr. Fei Sun from HKUST for helpful comments and acknowledge TCGA research network, Gregory M. Kiez and Mehmet Kutman Foundation, and the Yale University Department of Neurosurgery for providing access to sequencing data. This work was supported by grants from National Key Research and Development Plan (2016YFC0902500); Natural Science Foundation of China (NSFC)/Research Grants Council (RGC), Hong Kong, China Joint Research Scheme (81761168038 to T.J. and N_HKUST606/17 to J.W.); National Natural Science Foundation of China (81502495, 81502606, and 81702460); Capital Foundation of Medical Developments (2016-1-1072); Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (ZYLX201708); Beijing Nova Program (Z171100001117022); and Beijing Administration of Hospitals? Youth Program (QML20160502). J.W. was also supported by Collaborative Research Fund (CRF), Hong Kong (C6002-17GF); Hong Kong Epigenomics Project (LKCCFL18SC01-E); and HKUST start-up and initiation grants and received substantial support from BDBI Lab. D.-H.N. was supported by the grant of Korea Health Technology R&D project through KHIDI funded by the Ministry of Health & Welfare, Republic of Korea (HI14C3418). Funding Information: This work is a pilot study from the Chinese Glioma Genome Atlas (CGGA) and Asian Glioma Genome Atlas (AGGA) Research Networks. The authors would like to especially thank all contributors to CGGA and AGGA. The authors thank Dr. Fei Sun from HKUST for helpful comments and acknowledge TCGA research network, Gregory M. Kiez and Mehmet Kutman Foundation, and the Yale University Department of Neurosurgery for providing access to sequencing data. This work was supported by grants from National Key Research and Development Plan (2016YFC0902500); Natural Science Foundation of China (NSFC)/Research Grants Council (RGC), Hong Kong, China Joint Research Scheme (81761168038 to T.J. and N_HKUST606/17 to J.W.); National Natural Science Foundation of China (81502495, 81502606, and 81702460); Capital Foundation of Medical Developments (2016-1-1072); Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (ZYLX201708); Beijing Nova Program (Z171100001117022); and Beijing Administration of Hospitals{\textquoteright} Youth Program (QML20160502). J.W. was also supported by Collaborative Research Fund (CRF), Hong Kong (C6002-17GF); Hong Kong Epigenomics Project (LKCCFL18SC01-E); and HKUST start-up and initiation grants and received substantial support from BDBI Lab. D.-H.N. was supported by the grant of Korea Health Technology R&D project through KHIDI funded by the Ministry of Health & Welfare, Republic of Korea (HI14C3418). Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = nov,
day = "29",
doi = "10.1016/j.cell.2018.09.038",
language = "English",
volume = "175",
pages = "1665--1678.e18",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "6",
}
