The epidermal growth factor receptor in malignant gliomas: Pathogenesis and therapeutic implications
University of California, San Francisco, Department of Radiation Oncology, 1600 Divisadero Street, Suite H1031, San Francisco, CA 94143, USA. Expert Opinion on Therapeutic Targets
(Impact Factor: 5.14).
05/2007; 11(4):463-72. DOI: 10.1517/14728220.127.116.113
Activated epidermal growth factor receptor (EGFR) has emerged as an important therapeutic target for a variety of solid tumors, particularly malignant gliomas. Mutation or amplification of EGFR is commonly observed in malignant gliomas and these modifications are associated with increased cell proliferation and radiation resistance. Small-molecule kinase inhibitors targeting the intracellular kinase domain of the EGFR and monoclonal antibodies against the extracellular domain of the EGFR have demonstrated in vitro efficacy and have spawned clinical trials incorporating EGFR inhibition into the management of malignant gliomas, for example, combining EGFR inhibitors with radiation therapy. This early clinical experience indicates that EGFR inhibitors are well tolerated; however, it remains unclear how best to integrate EGFR inhibition into the management of malignant gliomas. As signaling pathways become better defined, patients may be treated with EGFR inhibitors based on the molecular features of their tumors and treatment efficacy may be improved by combining EGFR inhibition with other small kinase inhibitors and radiation therapy.
Available from: Sherry A Weppler
- "Epidermal Growth Factor Receptor (EGFR) overexpression or overactivation is also commonly observed in GBM tumors (40–70% of the patients) –. EGFR overexpression has been correlated with treatment resistance , as well as poor survival and poor prognosis . Further, it has been demonstrated that the expression of a specific mutant form of EGFR (EGFRvIII) promotes tumor formation and growth (reviewed in ). "
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ABSTRACT: The PI3K/AKT/mTOR pathway is commonly over activated in glioblastoma (GBM), and Rictor was shown to be an important regulator downstream of this pathway. EGFR overexpression is also frequently found in GBM tumors, and both EGFR and Rictor are associated with increased proliferation, invasion, metastasis and poor prognosis. This research evaluated in vitro and in vivo whether the combined silencing of EGFR and Rictor would result in therapeutic benefits. The therapeutic potential of targeting these proteins in combination with conventional agents with proven activity in GBM patients was also assessed. In vitro validation studies were carried out using siRNA-based gene silencing methods in a panel of three commercially available human GBM cell lines, including two PTEN mutant lines (U251MG and U118MG) and one PTEN-wild type line (LN229). The impact of EGFR and/or Rictor silencing on cell migration and sensitivity to chemotherapeutic drugs in vitro was determined. In vivo validation of these studies was focused on EGFR and/or Rictor silencing achieved using doxycycline-inducible shRNA-expressing U251MG cells implanted orthotopically in Rag2M mice brains. Target silencing, tumor size and tumor cell proliferation were assessed by quantification of immunohistofluorescence-stained markers. siRNA-mediated silencing of EGFR and Rictor reduced U251MG cell migration and increased sensitivity of the cells to irinotecan, temozolomide and vincristine. In LN229, co-silencing of EGFR and Rictor resulted in reduced cell migration, and increased sensitivity to vincristine and temozolomide. In U118MG, silencing of Rictor alone was sufficient to increase this line's sensitivity to vincristine and temozolomide. In vivo, while the silencing of EGFR or Rictor alone had no significant effect on U251MG tumor growth, silencing of EGFR and Rictor together resulted in a complete eradication of tumors. These data suggest that the combined silencing of EGFR and Rictor should be an effective means of treating GBM.
Available from: Wouter Caarls
- "Fig S1. In view of the upregulated Her1 (epidermal growth factor receptor) expression and/or gene dosage in >40% of all gliomas , , , , , ,  as well as in low grade oligodendroglial tumors , we postulate that a cocktail of QDs attached to several MAbs against EGFR as well as QD-EGF would unambiguously distinguish these gliomas from normal human brain. Other possible cell membrane epitopes that are upregulated on glioma cells compared to normal brain tissue are PDGFRα , and several integrins  which could also be considered for an even more general cocktail. "
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ABSTRACT: The current therapy of malignant gliomas is based on surgical resection, radio-chemotherapy and chemotherapy. Recent retrospective case-series have highlighted the significance of the extent of resection as a prognostic factor predicting the course of the disease. Complete resection in low-grade gliomas that show no MRI-enhanced images are especially difficult. The aim in this study was to develop a robust, specific, new fluorescent probe for glioma cells that is easy to apply to live tumor biopsies and could identify tumor cells from normal brain cells at all levels of magnification.
In this investigation we employed brightly fluorescent, photostable quantum dots (QDs) to specifically target epidermal growth factor receptor (EGFR) that is upregulated in many gliomas. Living glioma and normal cells or tissue biopsies were incubated with QDs coupled to EGF and/or monoclonal antibodies against EGFR for 30 minutes, washed and imaged. The data include results from cell-culture, animal model and ex vivo human tumor biopsies of both low-grade and high-grade gliomas and show high probe specificity. Tumor cells could be visualized from the macroscopic to single cell level with contrast ratios as high as 1000: 1 compared to normal brain tissue.
The ability of the targeted probes to clearly distinguish tumor cells in low-grade tumor biopsies, where no enhanced MRI image was obtained, demonstrates the great potential of the method. We propose that future application of specifically targeted fluorescent particles during surgery could allow intraoperative guidance for the removal of residual tumor cells from the resection cavity and thus increase patient survival.
Available from: Hauke Stephan Busch
- "Different EGF-R ligands (such as EGF and HB-EGF) are expressed by keratinocytes both at a basal level and as a result of HGF stimulation (data not shown). The EGF- R mediates cjun-dependent formation of the keratinocyte leading edge (Li et al, 2003; Zenz et al, 2003) and is also an important player during tumor development and progression (Burtness, 2007; Nakamura, 2007; Sharma et al, 2007). Likewise, PLAU-R has been shown in a mouse model to be positively correlated to tumor initiation and growth (Ploplis et al, 2007). "
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ABSTRACT: Translation of large-scale data into a coherent model that allows one to simulate, predict and control cellular behavior is far from being resolved. Assuming that long-term cellular behavior is reflected in the gene expression kinetics, we infer a dynamic gene regulatory network from time-series measurements of DNA microarray data of hepatocyte growth factor-induced migration of primary human keratinocytes. Transferring the obtained interactions to the level of signaling pathways, we predict in silico and verify in vitro the necessary and sufficient time-ordered events that control migration. We show that pulse-like activation of the proto-oncogene receptor Met triggers a responsive state, whereas time sequential activation of EGF-R is required to initiate and maintain migration. Context information for enhancing, delaying or stopping migration is provided by the activity of the protein kinase A signaling pathway. Our study reveals the complex orchestration of multiple pathways controlling cell migration.
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