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, Oct 06, 2015
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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.
    Frontiers in Oncology 03/2014; 4:47. DOI:10.3389/fonc.2014.00047
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    • "It has been shown that transactivation of c-Met by the epidermal growth factor receptor (EGFR) is an important contributing factor to aberrant c-Met signaling [17– 19] and depends on the direct association with active EGFR [20]. 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 GBM are 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 an HGF/c-Met-dependent GBM cell 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 expression was 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 with WP1193 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 signaling axis is enhanced by ΔEGFR through increased STAT3-dependent HGF expression and that targeting c-Met in Mes GBMs may be an important strategy for therapy.
    Neoplasia (New York, N.Y.) 01/2013; 15(1):73-84. · 4.25 Impact Factor
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    • "TKs, which are major inducers in GBM, exhibit crosstalk. The c-Met receptor is strongly phosphorylated as a function of EGFRvIII receptor levels, suggesting the presence of crosstalk between c-Met and EGFRvIII signaling, although the intermediary molecule has yet to be elucidated [77]. Axl RTK also follows a similar phosphorylation response as a function of EGFRvIII levels [77]. "
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    ABSTRACT: Glioblastoma multiforme (GBM), a WHO grade IV malignant glioma, is the most common and lethal primary brain tumor in adults; few treatments are available. Median survival rates range from 12-15 months. The biological characteristics of this tumor are exemplified by prominent proliferation, active invasiveness, and rich angiogenesis. This is mainly due to highly deregulated signaling pathways in the tumor. Studies of these signaling pathways have greatly increased our understanding of the biology and clinical behavior of GBM. An integrated view of signal transduction will provide a more useful approach in designing novel therapies for this devastating disease. In this review, we summarize the current understanding of GBM signaling pathways with a focus on potential molecular targets for anti-signaling molecular therapies.
    Cancers 12/2011; 3(3):3242-78. DOI:10.3390/cancers3033242
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