EGF receptor inhibitors in the treatment of glioblastoma multiform: Old clinical allies and newly emerging therapeutic concepts

Gadji, Macoura; Crous, Ana-Maria Tsanaclis; Fortin, David; Krcek, Jerry; Torchia, Mark G.; Mai, Sabine; Drouin, Régen; Klonisch, Thomas

doi:10.1016/j.ejphar.2009.10.010

Cited by 27 publications

(22 citation statements)

References 103 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Expression of OSM-induced STAT-3 target genes was inhibited by CX-4945 (Figure 2E). A bioinformatics analysis in glioma suggested CK2 could be downstream of EGFRvIII (35), the mutated oncogenic form of EGFR common in GBM (36). EGF can activate the STAT pathway (37); thus, we examined CK2 involvement in this system.…”

Section: Resultsmentioning

confidence: 99%

Targeting Protein Kinase CK2 Suppresses Prosurvival Signaling Pathways and Growth of Glioblastoma

Zheng

McFarland

Drygin

et al. 2013

Clinical Cancer Research

127

138

View full text Add to dashboard Cite

Purpose Gliomas are the most frequently occurring primary malignancies in the brain, and glioblastoma (GBM) is the most aggressive of these tumors. Protein kinase CK2 is composed of two catalytic subunits (α and/or α’) and two β regulatory subunits. CK2 suppresses apoptosis, promotes neo-angiogenesis, and enhances activation of the JAK/STAT, NF-κB, PI3K/AKT, Hsp90, Wnt and Hedgehog pathways. Aberrant activation of the NF-κB, PI3K/AKT and JAK/STAT-3 pathways is implicated in GBM progression. Since CK2 is involved in their activation, the expression and function of CK2 in GBM was evaluated. Experimental Design and Results Analysis of 537 GBMs from The Cancer Genome Atlas Project demonstrates the CSNK2A1 gene, encoding CK2α, has gene dosage gains in GBM (33.7%), and is significantly associated with the classical GBM subtype. Inhibition of CK2 activity by CX-4945, a selective CK2 inhibitor, or CK2 knockdown by siRNA suppresses activation of the JAK/STAT, NF-κB and AKT pathways and downstream gene expression in human GBM xenografts. On a functional level, CX-4945 treatment decreases the adhesion and migration of GBM cells, in part through inhibition of integrin β1 and α4 expression. In vivo, CX-4945 inhibits activation of STAT-3, NF-κB p65 and AKT, and promotes survival of mice with intracranial human GBM xenografts. Conclusions CK2 inhibitors may be considered for treatment of patients with GBM.

show abstract

Section: Resultsmentioning

confidence: 99%

Targeting Protein Kinase CK2 Suppresses Prosurvival Signaling Pathways and Growth of Glioblastoma

Zheng

McFarland

Drygin

et al. 2013

Clinical Cancer Research

127

138

View full text Add to dashboard Cite

show abstract

“…Inhibitors of EGFR or platelet-derived growth factor receptor (PDGFR) are being tested in phase 1/2 trials with and without radiation as well as in combination with conventional chemotherapy. 53 Imatinib (PDGFR inhibitor) has been associated in a phase 1 trial with increased incidence of intracranial hemorrhage, especially in patients with brainstem glioma, which requires further investigation. 54 Results from a phase 2 trial (HIT-GMB-D) using high-dose methotrexate showed results superior to that in the control groups, and therefore this regimen is being tested as a phase 3 study.…”

Section: Future Directionsmentioning

confidence: 99%

High-Grade Gliomas in Children

Cage¹,

Mueller²,

Haas‐Kogan³

et al. 2012

Neurosurgery Clinics of North America

View full text Add to dashboard Cite

High-grade gliomas (HGGs) are malignant tumors and typically include glioblastoma multiforme and anaplastic astrocytoma subtypes. Brainstem gliomas and ependymomas are separate entities with respect to clinical presentation, treatment, prognosis, and outcome in comparison with supratentorial HGGs. In children, these tumors account for 3% to 7% of newly diagnosed brain tumors and 20% of all diagnoses of pediatric supratentorial brain tumors. These neoplasms are highly proliferative and mitotically active and of glial origin. This article reviews clinical, diagnostic, and pathologic features of HGG and current treatments and potential future therapies specific to pediatric patients with HGGs.

show abstract

“…Recent reviews have summarized some of these approaches (36, 37). A recent discovery of isocitrate dehydrogenase (IDH) as being involved in earlier low-grade astrocytomas has also enhanced the possibility of the utility of metabolic approaches (38–41).…”

Section: Neuronal-astrocyte-vascular Metabolic Unit Vulnerabilities (mentioning

confidence: 99%

“…Intrinsic SVZ cells also demonstrate sensitivity to EGF, which they require for growth. In many instances, EGF receptors are either overexpressed or mutated into constitutively active receptors in astrocytomas, demonstrating a link to inherent stem cells (36). There have been a large number of clinical trials of astrocytoma treatments focusing on EGF receptors (36, 37).…”

Section: Neuronal-astrocyte-vascular Metabolic Unit Vulnerabilities (mentioning

confidence: 99%

“…In many instances, EGF receptors are either overexpressed or mutated into constitutively active receptors in astrocytomas, demonstrating a link to inherent stem cells (36). There have been a large number of clinical trials of astrocytoma treatments focusing on EGF receptors (36, 37). These observations support the idea that similarities may exist between astrocytoma cell and normal immature astrocyte metabolism, since they may have common cells of origin.…”

Section: Neuronal-astrocyte-vascular Metabolic Unit Vulnerabilities (mentioning

confidence: 99%

See 1 more Smart Citation

Neuronal-Astrocyte Metabolic Interactions: Understanding the Transition Into Abnormal Astrocytoma Metabolism

Turner

Adamson

2011

J Neuropathol Exp Neurol

112

View full text Add to dashboard Cite

Brain function depends upon complex metabolic interactions amongst only a few different cell types, with astrocytes providing critical support for neurons. Astrocyte functions include buffering the extracellular space, providing substrates to neurons, interchanging glutamate and glutamine for synaptic transmission with neurons, and facilitating access to blood vessels. Whereas neurons possess highly oxidative metabolism and easily succumb to ischemia, astrocytes rely more on glycolytic metabolism and hence are less susceptible to lack of oxygen. Astrocytoma cells appear to retain basic metabolic mechanisms of astrocytes, for example, they show a high glycolytic rate, lactate extrusion, ability to flourish under hypoxia, and opportunistic use of mechanisms to enhance cell division and maintain growth. Differences in metabolism between neurons and astrocytes may also extend to astrocytoma cells, providing therapeutic opportunities against astrocytomas, including sensitivity to acetate, a high rate of glycolysis and lactate extrusion, glutamate uptake transporters, differential sensitivities of monocarboxylate transporters, presence of glycogen, high interlinking with gap junctions, use of NADPH for lipid synthesis, utilizing different isoforms of synthetic enzymes (e.g. isocitrate dehydrogenase, pyruvate carboxylase, pyruvate kinase, lactate dehydrogenase) and different glucose uptake mechanisms. These unique metabolic susceptibilities may augment conventional therapeutic attacks based on cell division differences and surface receptors alone.

show abstract

EGF receptor inhibitors in the treatment of glioblastoma multiform: Old clinical allies and newly emerging therapeutic concepts

Cited by 27 publications

References 103 publications

Targeting Protein Kinase CK2 Suppresses Prosurvival Signaling Pathways and Growth of Glioblastoma

Targeting Protein Kinase CK2 Suppresses Prosurvival Signaling Pathways and Growth of Glioblastoma

High-Grade Gliomas in Children

Neuronal-Astrocyte Metabolic Interactions: Understanding the Transition Into Abnormal Astrocytoma Metabolism

Contact Info

Product

Resources

About