Prognostic Effect of Epidermal Growth Factor Receptor and EGFRvIII in Glioblastoma Multiforme Patients

Heimberger, Amy B.; Hlatky, Roman; Suki, Dima; Yang, David; Weinberg, Jeffrey S.; Gilbert, Mark R.; Sawaya, Raymond; Aldape, Kenneth

doi:10.1158/1078-0432.ccr-04-1737

Cited by 465 publications

(355 citation statements)

References 17 publications

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“…A follow-up phase III study that includes a blinded placebo control group is under consideration. This study will only include patients with tumors that express EGFRvIII, which typically includes 30-40% of the GBM population [67,68]. Finally, a phase III study was recently initiated to evaluate the use of an electromagnetic field generating device (Novocure) based on modest anti-tumor benefit observed among heavily pre-treated recurrent GBM patients [69].…”

Section: Overview Of the Marketmentioning

confidence: 99%

Cilengitide: An RGD Pentapeptide ανβ3 and ανβ5 Integrin Inhibitor in Development for Glioblastoma and Other Malignancies

et al. 2011

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Cilengitide, a cyclicized arginine-glycine-aspartic acid-containing pentapeptide, potently blocks 3 and 5 integrin activation. Integrins are upregulated in many malignancies and mediate a wide variety of tumor-stroma interactions. Cilengitide and other integrin-targeting therapeutics have preclinical activity against many cancer subtypes including glioblastoma (GBM), the most common and deadliest CNS tumor. Cilengitide is active against orthotopic GBM xenografts and can augment radiotherapy and chemotherapy in these models. In Phase I and II GBM trials, cilengitide and the combination of cilengitide with standard temozolomide and radiation demonstrate consistent antitumor activity and a favorable safety profile. Cilengitide is currently under evaluation in a pivotal, randomized Phase III study cancer subtypes including glioblastoma (GBM), the most common and deadliest central nervous system (CNS) tumor. Cilengitide is active against orthotopic GBM xenografts and can augment radiotherapy and chemotherapy in these models. In phase I and II GBM trials, cilengitide and the combination of cilengitide with standard temozolomide (TMZ) and radiation demonstrate consistent anti-tumor activity and a favorable safety profile. Cilengitide is currently under evaluation in a pivotal, randomized phase III study (CENTRIC) for newly diagnosed GBM. In addition, randomized, controlled phase II studies with cilengitide are ongoing for non-small cell lung cancer and squamous cell carcinoma of the head and neck.Cilengitide is the first integrin-inhibitor in clinical phase III development for oncology.

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Section: Overview Of the Marketmentioning

confidence: 99%

Cilengitide: An RGD Pentapeptide ανβ3 and ανβ5 Integrin Inhibitor in Development for Glioblastoma and Other Malignancies

et al. 2011

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“…The EGFRvIII mutant contains an in-frame deletion of amino acids 6 to 273, resulting in a ligand-independent, constitutively active oncoprotein. EGFRvIII expression has been linked to poor prognosis (23,24) and implicated in modulating radiosensitivity (25). Ionizing radiation in the therapeutic dose range of 1 to 5 Gy increases tyrosine phosphorylation of EGFR wild-type and EGFRvIII, activating mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways in Chinese hamster ovary cells (26).…”

Section: Introductionmentioning

confidence: 99%

Epidermal Growth Factor Receptor vIII Expression in U87 Glioblastoma Cells Alters Their Proteasome Composition, Function, and Response to Irradiation

Kim

Brush

Watson

et al. 2008

Molecular Cancer Research

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Little is known about the factors that influence the proteasome structures in cells and their activity, although this could be highly relevant to cancer therapy. We have previously shown that, within minutes, irradiation inhibits substrate degradation by the 26S proteasome in most cell types. Here, we report an exception in U87 glioblastoma cells transduced to express the epidermal growth factor receptor vIII (EGFRvIII) mutant (U87EGFRvIII), which does not respond to irradiation with 26S proteasome inhibition. This was assessed using either a fluorogenic substrate or a reporter gene, the ornithine decarboxylase degron fused to ZsGreen (cODCZsGreen), which targets the protein to the 26S proteasome. To elucidate whether this was due to alterations in proteasome composition, we used quantitative reverse transcription-PCR to quantify the constitutive (X, Y, Z) and inducible 20S subunits (Lmp7, Lmp2, Mecl1), and 11S (PA28A and B) and 19S components (PSMC1 and PSMD4). U87 and U87EGFRvIII significantly differed in expression of proteasome subunits, and in particular immunosubunits. Interestingly, 2 Gy irradiation of U87 increased subunit expression levels by 16% to 324% at 6 hours, with a coincident 30% decrease in levels of the proteasome substrate c-myc, whereas they changed little in U87EGFRvIII. Responses similar to 2 Gy were seen in U87 treated with a proteasome inhibitor, NPI0052, suggesting that proteasome inhibition induced replacement of subunits independent of the means of inhibition. Our data clearly indicate that the composition and function of the 26S proteasome can be changed by expression of the EGFRvIII. How this relates to the increased radioresistance associated with this cell line remains to be established. (Mol Cancer Res 2008;6(3):426 -34)

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“…An in-frame deletion of exons 2-7 of EGFR (referred to here as ΔEGFR), is the most commonly occurring mutant form of the EGFR in these tumors (4), is constitutively activated, and confers enhanced tumorigenicity to glioblastoma cells in vivo by reducing apoptosis and increasing proliferation (5)(6)(7). Patients with tumors expressing ΔEGFR have a poorer prognosis than those that do not (8,9).…”

mentioning

confidence: 99%

Mutant EGFR is required for maintenance of glioma growth in vivo, and its ablation leads to escape from receptor dependence

Mukasa¹,

Wykosky²,

Ligon

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Epidermal growth factor receptor (EGFR) gene amplification is the most common genetic alteration in high-grade glioma, and ≈50% of EGFR-amplified tumors also harbor a constitutively active mutant form of the receptor, ΔEGFR. Although ΔEGFR greatly enhances tumor growth and is thus an attractive target for anti-glioma therapies, recent clinical experiences with EGFR kinase inhibitors have been disappointing, because resistance is common and tumors eventually recur. Interestingly, it has not been established whether ΔEGFR is required for maintenance of glioma growth in vivo, and, by extension, if it truly represents a rational therapeutic target. Here, we demonstrate that in vivo silencing of regulatable ΔEGFR with doxycycline attenuates glioma growth and, therefore, that it is crucial for maintenance of enhanced tumorigenicity. Similar to the clinical experience, tumors eventually regained aggressive growth after a period of stasis, but interestingly, without re-expression of ΔEGFR. To determine how tumors acquired this ability, we found that a unique gene, KLHDC8, herein referred to as SΔE (Substitute for ΔEGFR Expression)-1, is highly expressed in these tumors, which have escaped dependence on ΔEGFR. SΔE-1 is also expressed in human gliomas and knockdown of its expression in ΔEGFR-independent "escaper" tumors suppressed tumor growth. Taken together, we conclude that ΔEGFR is required for both glioma establishment and maintenance, and that gliomas undergo selective pressure in vivo to employ alternative compensatory pathways to maintain aggressiveness in the event of EGFR silencing. Such alternative pathways function as substitutes for ΔEGFR signaling and should therefore be considered as potential targets for additional therapy.tumorigenicity | gliomblastoma | epidermal growth factor receptor

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Prognostic Effect of Epidermal Growth Factor Receptor and EGFRvIII in Glioblastoma Multiforme Patients

Cited by 465 publications

References 17 publications

Cilengitide: An RGD Pentapeptide ανβ3 and ανβ5 Integrin Inhibitor in Development for Glioblastoma and Other Malignancies

Cilengitide: An RGD Pentapeptide ανβ3 and ανβ5 Integrin Inhibitor in Development for Glioblastoma and Other Malignancies

Epidermal Growth Factor Receptor vIII Expression in U87 Glioblastoma Cells Alters Their Proteasome Composition, Function, and Response to Irradiation

Mutant EGFR is required for maintenance of glioma growth in vivo, and its ablation leads to escape from receptor dependence

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