Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Primary and secondary glioblastomas (pGBM, sGBM) are supposed to evolve through different genetic pathways, including EGF receptor and PDGF and its receptor and thus genes that are involved in tumor-induced angiogenesis. However, whether other angiogenic cytokines are also differentially expressed in these glioblastoma subtypes is not known so far, but this knowledge might be important to optimize an antiangiogenic therapy. Therefore, we studied the expression of several angiogenic cytokines, including VEGF-A, HGF, bFGF, PDGF-AB, PDGF-BB, G-CSF and GM-CSF in pGBMs and sGBMs as well as in gliomas WHO III, the precursor lesions of sGBMs. In tumor tissues, expression of all cytokines was observed albeit with marked differences concerning intensity and distribution pattern. Quantification of the cytokines in the supernatant of 30 tissue-corresponding glioma cultures revealed a predominant expression of VEGF-A in pGBMs and significantly higher expression levels of PDGF-AB in sGBMs. HGF and bFGF were determined in nearly all tumor cultures but with no GBM subtype or malignancy-related differences. Interestingly, GM-CSF and especially G-CSF were produced less frequently by tumor cells. However, GM-CSF secretion occurred together with an increased number of simultaneously secreted cytokines and correlated with a worse patient prognosis and may thus represent a more aggressive angiogenic phenotype. Finally, we confirmed an independent contribution of each tumor-derived cytokine analyzed to tumor-induced vascularization. Our data indicate that an optimal antiangiogenic therapy may require targeting of multiple angiogenic pathways that seem to differ markedly in pGBMs and sGBMs.
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PMID:Different angiogenic phenotypes in primary and secondary glioblastomas. 1633 29

Gliomas are the most common primary central nervous system tumours and about 55% are glioblastoma multiforme (GBM). Between 40% and 50% of GBM have dysregulated epidermal growth factor receptor (HER1/EGFR), and almost half of these co-express the mutant receptor subtype EGFRvIII, which may contribute to the aggressive and refractory course of GBM. Limited therapeutic options exist for GBM, and recurrence is common. Standard therapy is surgical resection, where possible, and radiotherapy. Adjuvant chemotherapy provides a modest survival benefit. New therapies are essential, and HER1/EGFR-targeted agents may provide a viable strategy. The HER1/EGFR tyrosine kinase inhibitors erlotinib and gefitinib are in advanced clinical development for glioma, and a number of trials are in progress, or have recently been completed. Preliminary results with gefitinib show no objective responses, but do provide evidence of disease control. In contrast, preliminary data with erlotinib appear more encouraging. Erlotinib inhibits wild-type HER1/EGFR and EGFRvIII, which may underlie its promising clinical activity. Other HER1/EGFR-targeted agents are also being investigated for glioma, including monoclonal antibodies, radio-immuno conjugates, ligand-toxin conjugates, antisense oligonucleotides and ribozymes. Further studies will define their clinical potential and hopefully provide new, effective treatments for GBM and other malignant brain tumours.
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PMID:Epidermal growth factor receptor inhibition for the treatment of glioblastoma multiforme and other malignant brain tumours. 1648 82

ZD1839 ("Iressa") is an orally active, selective epidermal growth factor (EGF) receptor-tyrosine kinase inhibitor. We evaluated the antitumor activity of ZD1839 in combination with HSP90 antagonist, 17-AAG in malignant human glioma cell lines. ZD1839 independently produced a dose-dependent inhibition of cellular proliferation in glioma cells grown in culture with time- and dose-dependent accumulation of cells in G(1) phase of the cell cycle on flow cytometric analysis, although the concentrations required for optimal efficacy were at or above the limits of clinically achievable levels. Because the heat shock protein (HSP) is involved in the conformational maturation of a number of signaling proteins critical to the proliferation of malignant glioma cells, we hypothesized that the HSP90 inhibitor 17-AAG would potentiate ZD 1839-mediated glioma cytotoxicity by decreasing the activation status of EGF receptor, as well as down regulating the levels of other relevant signaling effectors. We, therefore, examined the effects of ZD1839 and 17-AAG, alone and in combination, on signal transduction and apoptosis in a series of malignant glioma cell lines. Simultaneous exposure to these inhibitors significantly induced cell death and quantitative analysis revealed that interaction between ZD1839 and 17-AAG-induced cytotoxicity was synergistic, leading to a pronounced increase in active caspase-3 and PARP cleavage. No significant growth inhibition or caspase activation was seen in control cells. The enhanced cytotoxicity of this combination was associated with diminished Akt activation and a significant downregulation of EGFR receptor, Raf-1 and mitogen activated protein kinase (MAPK). Cells exposed to 17-AAG and ZD1839 displayed a significant reduction in cell cycle regulatory proteins, such as CDK4 and CDK6. Taken together, these findings suggest that ZD1839, an EGF receptor tyrosine kinase inhibitor, plays a critical role in regulating the apoptotic response to 17-AAG and that multi-site targeting of growth signaling and cell survival pathways could provide a potent strategy to treat patients with malignant gliomas.
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PMID:Cooperative inhibitory effect of ZD1839 (Iressa) in combination with 17-AAG on glioma cell growth. 1655 Jun 10

Nordy is a chiral compound synthesized based on the structure of a natural lipoxygenase (LO) inhibitor nordihydroguaiaretic acid (NDGA) from plants. The aim of the present study is to investigate the effect of Nordy on malignant human glioma cell responses to chemoattractants and growth promoting signals. We found that Nordy, in a non-cytotoxic concentration range, potently inhibited the chemotaxis and calcium flux of a human glioblastoma cell line U87 induced by a formylpeptide receptor (FPR) agonist, formyl-methionyl-leucyl-phenylalanine (fMLF) and epidermal growth factor (EGF). U87 cells treated by Nordy also showed a significantly impaired proliferation and expression of mRNA for vascular endothelial growth factor (VEGF) induced by fMLF. The chemotactic and proliferation responses of Nordy treated U87 cells to EGF were concomitantly diminished. Further experiments revealed that Nordy did not significantly affect FPR gene expression in U87 cells, but attenuated the activation of a plethora of signaling molecules including ERK1/2, p38, JNK, and Akt when the cells were stimulated by fMLF. EGF-induced EGF receptor phosphorylation was also inhibited in Nordy-treated U87 cells. Moreover, Nordy significantly reduced the tumorigenicity of U87 cells in nude mice. Our results suggest that Nordy is capable of inhibiting glioma cell responses to signals that promote cell motility, growth and production of VEGF. Thus, Nordy may constitute a molecular basis for the development of novel anti-cancer drugs.
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PMID:A novel lipoxygenase inhibitor Nordy attenuates malignant human glioma cell responses to chemotactic and growth stimulating factors. 1737 39

Amplified epidermal growth factor receptor (EGFR) signaling is supposed to contribute to clinical radiation resistance of glioblastoma multiforme (GBM). Therefore, inhibition of EGFR signaling pathways by the selective EGFR tyrosine kinase inhibitor, gefitinib (ZD1839, Iressa), may increase the therapeutic effects of radiotherapy. The effects of different schedules for administration of gefitinib on sensitivity to irradiation of the human glioma cell lines (251MG and SF-767), a rat glioma cell line (BT4C), and an immortalized rat brain endothelial cell line (RBE4) is reported. Differences in effects of the combined treatment on cell toxicity were determined by a fluorometric cytotoxicity assay, and nuclear DNA fragmentation was used for quantification of apoptosis. Pre-administration with gefitinib for 30 min prior to irradiation followed by continuous incubation with gefitinib significantly increased the cytotoxicity of SF-767, BT4C, and RBE4 cells. However, the human glioma cell line 251MG was protected against radiation-induced damage by this treatment schedule, at lower concentrations of gefitinib. Pre-administration with gefitinib for 24 h prior to irradiation without following incubation with gefitinib increased the cytotoxicity of SF-767 and BT4C cells. Post-irradiation treatment with gefitinib significantly increased the cytotoxicity in all cell lines except for 251MG. We demonstrated heterogeneity in the cytotoxic effects of gefitinib between cell lines. Response to gefitinib might be due to other mechanisms than through the EGF receptor as some of the cell lines showed sensitivity to gefitinib despite no or low expression of EGFR. This study also demonstrates the importance of timing of gefitinib administration when this agent is combined with irradiation.
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PMID:Treatment schedule is of importance when gefitinib is combined with irradiation of glioma and endothelial cells in vitro. 1791 26

We report a case of glioblastoma (GBM) occurring 8 years after radiation therapy for a medulloblastoma. A 15-year-old boy underwent surgery and radiotherapy for a medulloblastoma and 8 years later he developed a second tumor at the same site. The second lesion showed different histological and molecular features, was diagnosed as a glioblastoma and fulfilled the criteria of radiation-induced neoplasm. Mutational analysis of the p53 gene showed a C to G transition at codon 176 in tumor DNA. LOH was detected at 17p and 19q. The tumor also showed O6-methylguanine-DNA methyl-transferase (MGMT) promoter methylation and no amplification of EGF receptor. In conclusion, the radiation-induced MGMT hyper-methylation and p53 mutations may have a role in the development of a subgroup of radio-induced glioma (RIG), suggesting that these molecular alterations directly cooperate in the genesis of the post-irradiation GBM. Moreover RIGs seem to be a heterogeneous group of tumors that may resemble either primary or secondary GBM.
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PMID:Radiation-induced glioblastoma in a medulloblastoma patient: a case report with molecular features. 1838 14

Transgenic rats expressing v-erbB (viral form of the EGF receptor) under transcriptional regulation by the S100beta promoter develop brain tumors (Ohgaki et al. J Neuropathol Experimental Neurol 65: 1111-1117, 2006). In the present study, we carried out detailed immunohistochemical and ultrastructural characterization of the brain tumors that developed in these rats. Of 49 homozygous transgenic rats between 16 and 94 weeks of age (mean, 59 weeks), 31 rats were autopsied because they showed severe neurological symptoms and/or became moribund. Among these, 30 rats had brain tumors, which were classified histologically as malignant glioma, anaplastic oligodendroglioma, and low-grade oligodendroglioma. Six transgenic rats developed two different histologic types of brain tumor, which were considered to be of multiclonal origin, because of the lack of histological transitions. All brain tumors contained neoplastic cells immunoreactive for S100 and GFAP. Diffuse immunoreactivity for Olig2 and Nkx2.2 was observed in neoplastic cells in all seven anaplastic oligodendrogliomas and in all three low-grade oligodendrogliomas analyzed, but in none of 26 malignant gliomas. Electron microscopy, carried out on four malignant gliomas and four anaplastic oligodendrogliomas, revealed the presence of intermediate filament bundles devoid of side arms, indicating glial differentiation. There was no evidence of cilia, microvilli, neurosecretory granules, synaptic structures or neurofilaments, excluding the possibility of ependymal or neuronal tumors. The present study thus provides additional evidence that the brain tumors developing in S100beta-v-erbB transgenic rats are of glial origin, with or without oligodendroglial differentiation. Reproducible development of three distinct histologic types of brain tumor in unique localizations may be explained by activation of the v-erbB transgene driven by the S100beta promoter in specific precursor cells during development of the brain. Thus, S100beta-v-erbB transgenic rats may be useful to study the histogenesis and molecular mechanisms of development of glial tumors due to disruption of the EGFR pathway.
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PMID:Immunohistochemical and ultrastructural characterization of brain tumors in S100beta-v-erbB transgenic rats. 1849 86

The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is a central regulator of cell proliferation, migration, tumor growth, survival, angiogenesis and metabolism, contributing to the malignant phenotype of gliomas. Trials using targeted therapeutics against growth factor receptors and downstream signal mediators of the PI3K pathway have demonstrated only modest clinical benefit. Although recent clinical data suggests that malignant gliomas with PTEN are more likely to respond to EGF receptor inhibitors, gliomas have multiple concomitantly activated pathways, making them highly resistant to single-targeted therapy. This review discusses the importance of the PI3K pathway in glioma, the potential role of PTEN status in directing specific therapies, discusses clinical trial development of drug combinations to treat malignant gliomas and offers strategies for trial design that will be necessary to fully understand the successes and failures of current approaches to glioma therapy.
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PMID:Combination therapy for malignant glioma based on PTEN status. 1898 37

The anilino-quinazoline derivative BIBW-2992, which is being developed by Boehringer Ingelheim Corp for the potential treatment of solid tumors, is an oral dual receptor tyrosine kinase inhibitor of human EGF receptor (EGFR) and human epidermal growth factor receptor-2 (HER-2)/neu. EGFR and HER-2/neu activate numerous signaling pathways leading to cancer cell proliferation, survival and migration. In vitro, BIBW-2992 effectively and selectively inhibited EGFR and HER-2/neu and inhibited EGFR and HER-2/neu total tyrosine phosphorylation and tumor cell proliferation in vivo. Importantly, BIBW-2992 was active against tumors overexpressing EGFR with the secondary Thr790Met point mutation, which confers resistance to the first-generation EGFR inhibitors gefitinib and erlotinib. In phase I/II trials, BIBW-2992 was effective in patients with solid tumors, including those with NSCLC tumors activating mutations in the EGFR tyrosine kinase domain. BIBW-2992 was generally well tolerated with the main adverse effects being gastrointestinal or cutaneous disorders. At the time of publication, BIBW-2992 was undergoing phase II trials for NSCLC, breast and prostate cancers, head and neck carcinoma, as well as glioma. BIBW-2992 was granted Fast-Track status by the FDA for NSCLC and was investigated in phase III trials for this indication.
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PMID:BIBW-2992, a dual receptor tyrosine kinase inhibitor for the treatment of solid tumors. 1903 40

Gliomas are the most common and deadly form of malignant primary brain tumors. Loss of the tumor-suppressor PTEN and activation of the receptor tyrosine kinases (RTKs) EGF receptor, c-Met, PDGF receptor and VEGF receptor are among the most common molecular dysfunctions associated with glioma malignancy. PTEN interacts with RTK-dependent signaling at multiple levels. These include the ability of PTEN to counteract PI3K activation by RTKs, as well as possible effects of PTEN on RTK activation of the MAPK pathway and RTK-dependent gene-expression regulation. Consequently, PTEN expression affects RTK-induced malignancy. Importantly, the PTEN status was recently found to be critical for the outcome of RTK-targeted clinical therapies that have been developed recently. Combining RTK-targeted therapies with therapies aimed at counteracting the effects of PTEN loss, such as mTOR inhibition, might also have therapeutic advantage. This article reviews the known molecular and functional interactions between PTEN and RTK pathways and their implications for glioma therapy.
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PMID:Interactions between PTEN and receptor tyrosine kinase pathways and their implications for glioma therapy. 1919 61


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