Uncovering Therapeutic Targets FOR Glioblastoma: A Systems Biology Approach

Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Cell cycle (Georgetown, Tex.) (Impact Factor: 4.57). 09/2007; 6(22):2750-4. DOI: 10.4161/cc.6.22.4922
Source: PubMed


Even though glioblastoma, WHO grade IV (GBM) is one of the most devastating adult cancers, current treatment regimens have not led to any improvements in patient life expectancy or quality of life. The constitutively active EGFRvIII receptor is one of the most commonly mutated proteins in GBM and has been linked to radiation and chemotherapeutic resistance. To define the mechanisms by which this protein alters cell physiology, we have recently performed a phosphoproteomic analysis of EGFRvIII signaling networks in GBM cells. The results of this study provided important insights into the biology of this mutated receptor, including oncogene dose effects and differential utilization of signaling pathways. Moreover, clustering of the phosphoproteomic data set revealed a previously undescribed crosstalk between EGFRvIII and the c-Met receptor. Treatment of the cells with a combination employing both EGFR and c-Met kinase inhibitors dramatically decreased cell viability in vitro. In this perspective, we highlight the use of systems biology as a tool to better understand the molecular basis of GBM tumor biology as well as to uncover non-intuitive candidates for therapeutic target validation.

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Available from: Paul H Huang
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    • "Genomic and proteomic analyses have identified a number of key oncogenic drivers of glioblastoma multiforme (GBM) tumorigenesis and therapeutic resistance, including receptor tyrosine kinases (RTKs) (Beroukhim et al., 2007; Huang et al., 2007a,b). In particular, amplification of the epidermal growth factor receptor (EGFR) is present in approximately half of all GBMs (Hurtt et al., 1992; Jaros et al., 1992), with a large proportion also expressing activating mutations, such as deletion of exons 2–7, which results in a ligand-independent, constitutively active mutant commonly referred to as EGFR variant III (EGFRvIII) (Nishikawa et al., 1994; Batra et al., 1995; Huang et al., 1997). "
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    ABSTRACT: Glioblastoma Multiforme is the most aggressive and common form of adult brain cancer. Current therapeutic strategies include surgical resection followed by radiotherapy and chemotherapy. Despite such aggressive multi-modal therapy, prognosis remains poor with a median patient survival of 14 months. A proper understanding of the molecular drivers responsible for GBM progression are therefore necessary to instruct the development of novel targeted agents and to enable design of effective treatment strategies. Activation of the c-jun-N-terminal kinase isoform 2 (JNK2) is reported in primary brain cancers where it associates with histological grade and amplification of the epidermal growth factor receptor (EGFR). In this manuscript, we demonstrate an important role for JNK2 in the tumor promoting and invasive capacity of EGFR variant III (EGFRvIII), a constitutively active mutant form of the receptor commonly found in GBM. Expression of EGFRvIII induces transactivation of JNK2 in GBM cells that is required for a tumorigenic phenotype in vivo. Furthermore, JNK2 expression and activity is required to promote increased cellular invasion through stimulation of an HGF-c-Met signaling circuit whereby secretion of this extracellular ligand activates the RTK in both a cell autonomous and non-autonomous manner. Collectively, these findings demonstrate the co-operative and parallel activation of multiple RTKs in GBM and suggests that the development of selective JNK2 inhibitors could be therapeutically beneficial either as single agents or in combination with inhibitors of EGFR and/or c-Met.
    Full-text · Article · Oct 2015 · Molecular pharmacology
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    • "Interestingly, in vitro models have suggested that GBM cells expressing EGFRvIII are resistant to small molecule tyrosine kinase inhibitors (109). EGFRvIII signals to a mTOR complex 2 induced mechanism (110), thereby differing from the EGFR-mTOR complex 1 signaling axis, which may contribute to such therapy resistance. "
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    ABSTRACT: It is increasingly clear that both adult and pediatric glial tumor entities represent collections of neoplastic lesions, each with individual pathological molecular events and treatment responses. In this review, we discuss the current prognostic biomarkers validated for clinical use or with future clinical validity for gliomas. Accurate prognostication is crucial for managing patients as treatments may be associated with high morbidity and the benefits of high risk interventions must be judged by the treating clinicians. We also review biomarkers with predictive validity, which may become clinically relevant with the development of targeted therapies for adult and pediatric gliomas.
    Full-text · Article · Mar 2014 · Frontiers in Oncology
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    • "In GBMs, approximately 40% of tumors overexpressing wild-type EGFR coexpress a 2-to 7-exon deletion mutant of the EGFR, known as the ΔEGFR or EGFRvIII [21]. This cancer-specific mutant signals constitutively at a low level in a ligand-independent manner, owing to inefficient receptor dimerization [22] [23] [24], internalization, and down-regulation [25] [26]. "
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    ABSTRACT: The hepatocyte growth factor receptor (c-Met) and a constitutively active mutant of the epidermal growth factor receptor (ΔEGFR/EGFRvIII) are frequently overexpressed in glioblastoma (GBM) and promote tumorigenesis. The mechanisms underlying elevated hepatocyte growth factor (HGF) production in GBMare not understood. We found higher, coordinated mRNA expression levels of HGF and c-Met in mesenchymal (Mes) GBMs, a subtype associated with poor treatment response and shorter overall survival. In anHGF/c-Met–dependentGBMcell line, HGF expression declined upon silencing of c-Met using RNAi or by inhibiting its activity with SU11274. Silencing c-Met decreased anchorage-independent colony formation and increased the survival of mice bearing intracranial GBM xenografts. Consistent with these findings, c-Met activation by ΔEGFR also elevated HGF expression, and the inhibition of ΔEGFR with AG1478 reduced HGF levels. Interestingly, c-Met expressionwas required for ΔEGFR-mediated HGF production, anchorage-independent growth, and in vivo tumorigenicity, suggesting that these pathways are coupled. Using an unbiased mass spectrometry–based screen, we show that signal transducer and activator of transcription 3 (STAT3) Y705 is a downstream target of c-Met signaling. Suppression of STAT3 phosphorylation withWP1193 reduced HGF expression in ΔEGFR-expressing GBM cells, whereas constitutively active STAT3 partially rescued HGF expression and colony formation in c-Met knockdown cells expressing ΔEGFR. These results suggest that the c-Met/HGF signal- ing axisisenhancedby ΔEGFR through increased STAT3-dependent HGF expression and that targeting c-Met in Mes GBMs may be an important strategy for therapy.
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