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

Abstract

Graphical AbstractHighlights d Characterization of the mutational landscape of secondary glioblastoma d Clonal and subclonal METex14 promote glioma progression and mark worse prognosis d PLB-1001 is a highly selective, efficient, and BBB-permeable MET kinase inhibitor d PLB-1001 provides a safe and efficacious therapeutic approach for glioma treatment 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.

Chinese Glioma Genome Atlas (CGGA): A Comprehensive Resource with Functional Genomic Data for Chinese Glioma Patients

“…Statistics such as sequencing depth and coverage were calculated based on the resulting BAM files. SAVI2 was used to identify somatic mutations (including single-nucleotide variations and short insertions/deletions) as previously described [7, 8]. Briefly, in this pipeline, SAMtools mpileup and bcftools (version 0.1.19) [28] were employed to perform variant calling, and the preliminary variant list was filtered to remove positions with no sufficient sequencing depth, positions with only low-quality reads, and positions biased toward either strand.…”

“…Despite advances in current treatment standards, the survival rate of patients with glioma has not changed in decades, especially for aggressive gliomas (with a poor median survival time of only 12 to 14 months) [5, 6]. In addition, most lower-grade gliomas (grade II and III, LGG) will progress to glioblastoma (grade IV, GBM) in less than 10 years [4, 7, 8]. At present, the reasons for glioma recurrence or malignant progression may be as follows: 1) infiltrative tumour cells cannot be completely removed by neurosurgical resection [9, 10]; 2) retained tumour cells cannot be effectively suppressed by limited postoperative treatment options [3, 11, 12]; 3) multiple lesions may develop [13, 14]; 4) cell cloning is rapid under chemotherapy and/or radiotherapy [7, 15]; 5) the adaptive tumour microenvironment permits tumour cells [16, 17]; and 6) limited data resources lead to limited research.…”

Prognostic significance of age related genes in patients with lower grade glioma

“…Molecular profiles, like gene expression portraits, DNA mutation signatures and DNA methylation Ivyspring International Publisher characteristics are quite associated with the clinical overall survival of tumor patients [15][16][17][18][19]. Similar dataset is established in the Chinese Glioma Genome Atlas (CGGA) to provide massive amounts of data for basic and clinical research of glioma [20][21][22]. With the available TCGA, CGGA and Gene Expression Omnibus (GEO) datasets, here, we systematically define the molecular characteristics of age related genes and reveal their prognostic effects in determining the clinical overall survival of tumor patients, particularly LGG patients.…”

Metabolic Reprogramming by c-MET Inhibition as a Targetable Vulnerability in Glioblastoma

“…Similar to the observations in melanoma, our group made the recent and related discovery that in glioblastoma targeting MET signaling, a receptor kinase that connects to the ERK signaling pathway, elicits an increase of oxidative metabolism through activation of fatty acid oxidation (FAO) [6]. MET signaling remains a critical pathway in glioblastomas, but thus far akin to other molecular targets therapeutics targeting of MET fell rather short of expectations [7,8]. The causes are multiple and include the fact that inhibitors may not cross the blood brain barrier very well.…”