High levels of c-Met is associated with poor prognosis in glioblastoma

Petterson, Stine Asferg; Dahlrot, Rikke Hedegaard; Hermansen, Simon Kjær; Munthe, Sune; Gundesen, Michael; Wohlleben, Helle; Rasmussen, Tine; Beier, Christoph P.; Hansen, Steinbjørn; Kristensen, Bjarne Winther

doi:10.1007/s11060-015-1723-3

Cited by 62 publications

(59 citation statements)

References 38 publications

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“…MET is commonly dysregulated in GBM via various mechanisms including somatic mutations, rearrangement, amplification and overexpression of MET and HGF that leads to autocrine loop formation (10)(11)(12). Furthermore, MET expression inversely correlates with patient survival (12,13) and is upregulated in GBM (5,14,15).…”

Section: Introductionmentioning

confidence: 99%

Discovery and Therapeutic Exploitation of Mechanisms of Resistance to MET Inhibitors in Glioblastoma

Cruickshanks

Zhang

Hine

et al. 2019

Clinical Cancer Research

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Glioblastoma (GBM) is the most common and most lethal primary malignant brain tumor. The receptor tyrosine kinase MET is frequently upregulated or overactivated in GBM. Although clinically applicable MET inhibitors have been developed, resistance to single modality anti-MET drugs frequently occurs, rendering these agents ineffective. We aimed to determine the mechanisms of MET inhibitor resistance in GBM and use the acquired information to develop novel therapeutic approaches to overcome resistance. We investigated two clinically applicable MET inhibitors: crizotinib, an ATP-competitive small molecule inhibitor of MET, and onartuzumab, a monovalent monoclonal antibody that binds to the extracellular domain of the MET receptor. We developed new MET inhibitor-resistant cells lines and animal models and used reverse phase protein arrays (RPPA) and functional assays to uncover the compensatory pathways in MET inhibitor-resistant GBM. We identified critical proteins that were altered in MET inhibitor-resistant GBM including mTOR, FGFR1, EGFR, STAT3, and COX-2. Simultaneous inhibition of MET and one of these upregulated proteins led to increased cell death and inhibition of cell proliferation in resistant cells compared with either agent alone. In addition, treatment of mice bearing MET-resistant orthotopic xenografts with COX-2 or FGFR pharmacological inhibitors in combination with MET inhibitor restored sensitivity to MET inhibition and significantly inhibited tumor growth. These data uncover the molecular basis of adaptive resistance to MET inhibitors and identify new FDA-approved multidrug therapeutic combinations that can overcome resistance.

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Section: Introductionmentioning

confidence: 99%

Discovery and Therapeutic Exploitation of Mechanisms of Resistance to MET Inhibitors in Glioblastoma

Cruickshanks

Zhang

Hine

et al. 2019

Clinical Cancer Research

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“…Six studies 16, 17, 20-23 , conducted in Denmark, Japan, China, Korea, Turkey, involving 503 patients were available for this meta-analysis. The published years of studies ranged from 1998 to 2015.…”

Section: Resultsmentioning

confidence: 99%

Prognostic Role of c-Met Overexpression in High Grade Glioma: a Meta-analysis

Zhong

et al. 2019

Preprint

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4Objectives: This study aims to assess the relationship between the expression of c-Met 5 and the prognosis of high grade glioma patients. 6 Method: The MET proto-oncogene encoded c-Met protein. The gene expression data 7 of 325 patients were downloaded from CGGA. The Oncomine database analysis and 8 the prognosis analysis were conducted. Besides, meta-analysis was also performed to 9 confirm the conclusion. 10 Result: Oncomine database was identified and analyzed and results showed that the 11 MET copy number was obviously higher in glioblastoma than normal tissue 12 consistently (p<0.001). The prognostic analysis of 325 high grade glioma samples 13 showed that high c-Met expression patients had poor overall survival (OS) and 14 progression free survival (PFS) than the low c-Met expression patients dramatically 15 (HR, 2.223; 95% CI: 1.662 to 2.974; P<0.0001 and HR, 2.089; 95% CI: 1.578 to 2.770; 16 P<0.0001). 6 studies involving 503 patients were included in the meta-analysis. The 17 pooled results indicated that the high expression of c-Met was not significantly 18 associated with OS (HR =1.01, 95% CI:0.93-1.09), but strongly connected with shorter 19 PFS (HR =1.92, 95% CI:1.42-2.58, p<0.01). 20 Conclusion: c-Met overexpression has correlation with poor prognosis of high grade 21 glioma patients.22

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“…In the present study, we report that (in contrast to ‘standard’ astrocytomas) GCAs share a specific common trait, recognizable through the coexpression of three mesenchymal/radioresistance‐related markers: c‐Met, YKL‐40, and Cav1. MET gains have been observed in ~45% of GBMs, and c‐Met tumour expression identifies a subpopulation of GBMs associated with a significantly shorter survival as a consequence of poor response to ionizing radiation . YKL‐40 has been reported to predict resistance to radiochemotherapy, to promote angiogenesis, and to identify GBM patients with a poor prognosis .…”

Section: Discussionmentioning

confidence: 99%

“…MET gains have been observed in ~45% of GBMs, and c-Met tumour expression identifies a subpopulation of GBMs associated with a significantly shorter survival as a consequence of poor response to ionizing radiation. [24][25][26][27][28][29] YKL-40 has been reported to predict resistance to radiochemotherapy, to promote angiogenesis, and to identify GBM patients with a poor prognosis. [30][31][32][33] Cav1 expression, as previously reported by our group, appears to play an unfavourable prognostic role in gliomas, and its involvement in cancer cell radiochemoresistance has been increasingly explored in recent years.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal/radioresistant traits in granular astrocytomas: evidence from a combined clinical and molecular approach

Senetta

Mellai²,

Manini

et al. 2016

Histopathology

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Objective: To report clinical and dosimetric outcomes of a consecutive series of patients with anal cancer treated with volumetric-modulated arc therapy (VMAT) concomitant to chemotherapy (CT). Methods: A cohort of 39 patients underwent VMAT employing a schedule consisting of 50.4 Gy/28 fractions to the gross tumour volume (GTV) and 42 Gy/28 fractions to the elective nodal volumes for patients with cT2N0 disease. Patients with cT3-T4/N0-N3 tumours were prescribed 54 Gy/30 fractions to the GTV and 50.4 Gy/30 fractions to the gross nodal volumes if sized #3 cm or 54 Gy/30 fractions if . 3 cm. Elective nodal regions were given 45 Gy/30 fractions. CT was administered concurrently following Nigro's regimen. The primary end point was acute toxicity. Secondary end points were colostomy-free survival (CFS), disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS). Dosimetric data are also provided.Results: Median follow-up was 21 months. Maximum acute toxicities were: dermatologic-G3: 18%; gastrointestinal-G3: 5%; genitourinary-G3: 2%; anaemia-G2: 7%; leukopenia-G3: 28%; G4: 8%; neutropenia-G3: 13%; G4: 18%; thrombocytopenia-G3: 11%; and G4: 2%. The actuarial 2-year CFS was 77.9% [95% confidence interval (CI): 54-90.4%]. Actuarial 2-year OS and CSS were 85.2% (95% CI: 60.1-95.1%), while DFS was 75.1% (95% CI: 52.4.7-88.1%). Conclusion: Our clinical results support the use of VMAT as a safe and effective intensity-modulated radiotherapy (IMRT) option in the combined modality treatment of anal cancer, with consistent dosimetry, mild toxicity and promising sphincter preservation and survival rates. Advances in knowledge: IMRT is a standard of care for patients with anal cancer, and VMAT is a robust technical solution in this setting.

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High levels of c-Met is associated with poor prognosis in glioblastoma

Cited by 62 publications

References 38 publications

Discovery and Therapeutic Exploitation of Mechanisms of Resistance to MET Inhibitors in Glioblastoma

Discovery and Therapeutic Exploitation of Mechanisms of Resistance to MET Inhibitors in Glioblastoma

Prognostic Role of c-Met Overexpression in High Grade Glioma: a Meta-analysis

Mesenchymal/radioresistant traits in granular astrocytomas: evidence from a combined clinical and molecular approach

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