Overexpression of HGF/MET axis along with p53 inhibition induces de novo glioma formation in mice

Qin, Yuan; Musket, Anna; Kou, Jianqun; Preiszner, J.; Tschida, Barbara R.; Qin, Anna; Land, Craig A.; Staal, Ben; Kang, Liang; Tanner, Kirk; Jiang, Yong; Schweitzer, John B.; Largaespada, David A.; Xie, Qian

doi:10.1093/noajnl/vdaa067

Cited by 7 publications

(6 citation statements)

References 40 publications

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“…During normal neurogenesis, neural stem cells (NSCs) are primarily located in the hippocampus and subventricular zone (SVZ) where they proliferate into multi-lineage progenitor cells and differentiate into neurons, astrocytes, and oligodendrocytes to populate the nervous system. 21 However, glioma stem cells (GSCs) may arise from normal NSCs or neural progenitor cells that harbor genetic alterations, such as amplifications and mutations, resulting in oncogene overexpression and leading to gliomagenesis. Early studies of EGFR signaling showed that neural progenitors from the adult SVZ respond to EGFR activation with enhanced proliferation and migration.…”

Section: Genetic Rtk Alteration and Gliomagenesismentioning

confidence: 99%

“… 40 With MET RTK, Qin et al demonstrated that transgenic mice overexpressing the human HGF/MET axis along with p53 inhibition induced GBM in mice. 21 Moreover, in mice deficient in the tumor suppressor genes Ink4b and Arf irradiation-induced DNA damage triggered glioma formation with Met amplification as the most significant oncogenic event. 41 In all these 3 animal models, glioma arising from EGFR vIII or MET activation expressed GSC markers, supporting the concept that transforming NSCs into GSCs is critical to GBM development.…”

Section: Genetic Rtk Alteration and Gliomagenesismentioning

confidence: 99%

“…MET has been a promising druggable target in many cancer types for decades and is well-known for promoting cancer proliferation and invasion. 80 Recent studies not only show that multiple MET genetic alterations are found in GBM and are associated to poor prognosis, but also that activation of the HGF/MET axis contributes to gliomagenesis 21 , 41 ( Table 1 ). As described above, inhibiting the angiogenesis pathway through VEGF sequestration results in MET activation, converting glioma into a more invasive phenotype.…”

Section: Targeted Therapeutics Against Rtks In Gbmmentioning

confidence: 99%

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Receptor tyrosine kinases as druggable targets in glioblastoma: Do signaling pathways matter?

Qin

Musket

Musich

et al. 2021

Neuro-Oncology Advances

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Glioblastoma (GBM) is the most malignant primary brain tumor without effective therapies. Since bevacizumab was FDA approved for targeting vascular endothelial growth factor receptor 2 (VEGFR2) in adult patients with recurrent GBM, targeted therapy against receptor tyrosine kinases (RTKs) has become a new avenue for GBM therapeutics. In addition to VEGFR, the epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), hepatocyte growth factor receptor (HGFR/MET), and fibroblast growth factor receptor (FGFR) are major RTK targets. However, results from clinical Phase II/III trials indicate that most RTK-targeting therapeutics including tyrosine kinase inhibitors (TKIs) and neutralizing antibodies lack clinical efficacy, either alone or in combination. The major challenge is to uncover the genetic RTK alterations driving GBM initiation and progression, as well as to elucidate the mechanisms toward therapeutic resistance. In this review, we will discuss the genetic alterations in these five commonly targeted RTKs, the clinical trial outcomes of the associated RTK-targeting therapeutics, and the potential mechanisms toward the resistance. We anticipate that future design of new clinical trials with combination strategies, based on the genetic alterations within an individual patient’s tumor and mechanisms contributing to therapeutic resistance after treatment, will achieve durable remissions and improve outcomes in GBM patients

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Section: Genetic Rtk Alteration and Gliomagenesismentioning

confidence: 99%

Section: Genetic Rtk Alteration and Gliomagenesismentioning

confidence: 99%

Section: Targeted Therapeutics Against Rtks In Gbmmentioning

confidence: 99%

See 1 more Smart Citation

Receptor tyrosine kinases as druggable targets in glioblastoma: Do signaling pathways matter?

Qin

Musket

Musich

et al. 2021

Neuro-Oncology Advances

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“…SB has also been used to study RTK activity in gliomas; Qin et al. injected SB plasmids with HGF and MET cDNA as well as shRNA against p53 into lateral ventricles of neonatal mice and saw MET -driven glioma development ( 39 ). They tested two MET inhibitors, V-4084 and SGX523, and found sensitivity to both in isolated neurosphere cell lines.…”

Section: Genetically Engineered Mouse Models (Gemm)mentioning

confidence: 99%

Receptor tyrosine kinase (RTK) targeting in pediatric high-grade glioma and diffuse midline glioma: Pre-clinical models and precision medicine

et al. 2022

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Pediatric high-grade glioma (pHGG), including both diffuse midline glioma (DMG) and non-midline tumors, continues to be one of the deadliest oncologic diagnoses (both henceforth referred to as “pHGG”). Targeted therapy options aimed at key oncogenic receptor tyrosine kinase (RTK) drivers using small-molecule RTK inhibitors has been extensively studied, but the absence of proper in vivo modeling that recapitulate pHGG biology has historically been a research challenge. Thankfully, there have been many recent advances in animal modeling, including Cre-inducible transgenic models, as well as intra-uterine electroporation (IUE) models, which closely recapitulate the salient features of human pHGG tumors. Over 20% of pHGG have been found in sequencing studies to have alterations in platelet derived growth factor-alpha (PDGFRA), making growth factor modeling and inhibition via targeted tyrosine kinases a rich vein of interest. With commonly found alterations in other growth factors, including FGFR, EGFR, VEGFR as well as RET, MET, and ALK, it is necessary to model those receptors, as well. Here we review the recent advances in murine modeling and precision targeting of the most important RTKs in their clinical context. We additionally provide a review of current work in the field with several small molecule RTK inhibitors used in pre-clinical or clinical settings for treatment of pHGG.

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“…HGF/MET overexpression frequently occur in GBM patients and is associated with poor prognosis [54,79,80]. Using a transgenic mouse model, Qin et al [81] showed that overexpression of HGF and MET may transform neuro stem cells into glioma stem cells (GSCs), leading to GBM initiation. GBM harboring MET amplification or HGF autocrine activation are sensitive to MET inhibitors in preclinical models [82,83], recent clinical trials further showed that a combination of MET and VEGF inhibitors (ontarzucimab plus bevacizumab vs. placebo plus bevacizumab) significantly improved progression free survival (PFS) and overall survival (OS) in the mesenchymal subtype of recurrent GBM patients with high tumor HGF expression [84].…”

Section: Metmentioning

confidence: 99%

Chimeric antigen receptor T-cell therapy in glioblastoma: charging the T cells to fight

et al. 2020

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Glioblastoma multiforme (GBM) is the most common malignant brain cancer that invades normal brain tissue and impedes surgical eradication, resulting in early local recurrence and high mortality. In addition, most therapeutic agents lack permeability across the blood brain barrier (BBB), further reducing the efficacy of chemotherapy. Thus, effective treatment against GBM requires tumor specific targets and efficient intracranial drug delivery. With the most recent advances in immunotherapy, genetically engineered T cells with chimeric antigen receptors (CARs) are becoming a promising approach for treating cancer. By transducing T lymphocytes with CAR constructs containing a tumor-associated antigen (TAA) recognition domain linked to the constant regions of a signaling T cell receptor, CAR T cells may recognize a predefined TAA with high specificity in a non-MHC restricted manner, and is independent of antigen processing. Active T cells can travel across the BBB, providing additional advantage for drug delivery and tumor targeting. Here we review the CAR design and technical innovations, the major targets that are in pre-clinical and clinical development with a focus on GBM, and multiple strategies developed to improve CAR T cell efficacy.

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Overexpression of HGF/MET axis along with p53 inhibition induces de novo glioma formation in mice

Cited by 7 publications

References 40 publications

Receptor tyrosine kinases as druggable targets in glioblastoma: Do signaling pathways matter?

Receptor tyrosine kinases as druggable targets in glioblastoma: Do signaling pathways matter?

Receptor tyrosine kinase (RTK) targeting in pediatric high-grade glioma and diffuse midline glioma: Pre-clinical models and precision medicine

Chimeric antigen receptor T-cell therapy in glioblastoma: charging the T cells to fight

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