Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Elongation factor-2 kinase (eEF-2 kinase; Ca(2+)/calmodulin-dependent kinase III) controls the rate of peptide chain elongation. The activity of eEF-2 kinase is increased in many malignancies, yet its precise function in carcinogenesis remains unknown. Autophagy, a well-defined survival pathway in yeast, may also play an important role in oncogenesis. Furthermore, the autophagic response to nutrient deprivation is regulated by the mammalian target of rapamycin (mTOR). eEF-2 kinase lies downstream of mTOR and is regulated by several kinases in this pathway. Therefore, we studied the role of eEF-2 kinase in autophagy. Knockdown of eEF-2 kinase by RNA interference inhibited autophagy in several cell types as measured by light chain 3 (LC3)-II formation, acidic vesicular organelle staining, and electron microscopy. In contrast, overexpression of eEF-2 kinase increased autophagy. Furthermore, inhibition of autophagy markedly decreased the viability of glioblastoma cells grown under conditions of nutrient depletion. These results suggest that eEF-2 kinase plays a regulatory role in the autophagic process in tumor cells and may promote cancer cell survival under conditions of nutrient deprivation. Therefore, eEF-2 kinase activation may be a part of a survival mechanism in glioblastoma, and targeting this kinase may represent a novel approach to cancer treatment.
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PMID:Elongation factor-2 kinase: its role in protein synthesis and autophagy. 1692 Dec 68

Glioblastoma is a severe type of primary brain tumor, and its highly invasive character is considered to be a major therapeutic obstacle. Several recent studies have reported that ionizing radiation (IR) enhances the invasion of tumor cells, but the mechanisms for this effect are not well understood. In this study, we investigated the possible signaling mechanisms involved in IR-induced invasion of glioma cells. IR increased the matrix metalloproteinase (MMP)-2 promoter activity, mRNA transcription, and protein secretion along with the invasiveness of glioma cells lacking functional PTEN (U87, U251, U373, and C6) but not those harboring wild-type (WT)-PTEN (LN18 and LN428). IR activated phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin, and blockade of these kinases by specific inhibitors (LY294002, Akt inhibitor IV, and rapamycin, respectively) and transfection of dominant-negative (DN) mutants (DN-p85 and DN-Akt) or WT-PTEN suppressed the IR-induced MMP-2 secretion in U251 and U373 cells. In addition, inhibitors of epidermal growth factor receptor (EGFR; AG490 and AG1478), Src (PP2), and p38 (SB203580), EGFR neutralizing antibody, and transfection of DN-Src and DN-p38 significantly blocked IR-induced Akt phosphorylation and MMP-2 secretion. IR-induced activation of EGFR was suppressed by PP2, whereas LY294002 and SB203580 did not affect the activations of p38 and PI3K, respectively. Finally, these kinase inhibitors significantly reduced the IR-induced invasiveness of these cells on Matrigel. Taken together, our findings suggest that IR induces Src-dependent EGFR activation, which triggers the p38/Akt and PI3K/Akt signaling pathways, leading to increased MMP-2 expression and heightened invasiveness of PTEN mutant glioma cells.
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PMID:Ionizing radiation enhances matrix metalloproteinase-2 secretion and invasion of glioma cells through Src/epidermal growth factor receptor-mediated p38/Akt and phosphatidylinositol 3-kinase/Akt signaling pathways. 1695 Nov 63

Temsirolimus (CCI779), an intravenous analog of rapamycin, presents immunosuppressive properties and also antiproliferative activity. Its principal target is the mTOR serine/threonin kinase which controls the initiation of the transcription of many ARNm implicated in carcinogenesis. Breast cancers, glioblastoma and renal cell carcinoma were particularly studied with response rates from 10 to 20 %. In haematology, mantle-cell lymphoma is of particular interest because of constitutional activation of cyclin D1 (response rate of 40 %). As a whole these data define temsirolimus as a promising new drug. Current and further developments are based on its association with chemotherapy in a concomitant or sequential way.
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PMID:[Update on clinical activity of CCI779 (temsirolimus), mTOR inhibitor]. 1714 84

Regulated gene expression may be required for the clinical development of certain gene therapies. Several approaches have been developed that allow pharmacologic control of transgene expression, including the dimerizer-regulated transcriptional system in which rapamycin or its analogs function as transcriptional inducers. These compounds can also act as direct antitumor agents via inhibition of mammalian target of rapamycin (mTOR). We describe the development of an optimized recombinant adeno-associated virus (AAV) expression cassette that allows dimerizer-regulated gene expression from a single vector in vitro and in vivo. After demonstrating multiple cycles of rapamycin-dependent transgene induction following a single administration of an AAV vector in vivo, application of this regulated AAV gene expression system to the pharmacologic control of antiangiogenic therapy was evaluated in preclinical tumor models. Dimerizer-regulated vectors were constructed encoding a soluble inhibitor of the vascular endothelial growth factor (VEGF) pathway. In two subcutaneous models of glioblastoma, regulated expression of the VEGF inhibitor via recombinant AAV-mediated gene transfer, in combination with rapamycin, was shown to decrease tumor growth rate significantly. The dual properties of rapamycin--as a transcriptional inducer and mTOR inhibitor--are exploited in combination with an AAV-encoded antiangiogenic agent to provide a novel approach for the treatment of malignant diseases.
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PMID:Rapamycin-regulated control of antiangiogenic tumor therapy following rAAV-mediated gene transfer. 1724 54

Receptor tyrosine kinases expressed in endothelial cells are potential targets for therapy with specific tyrosine kinase inhibitors. Endothelial cell KIT expression has not been systematically evaluated in human cancer. In the present study, endothelial cell KIT expression was assessed in 345 tumours consisting of 34 different histological types using a tissue microarray technique. Marked KIT expression occurred in the tumour endothelial cells only in primary glioblastomas in the microarray. Moderate to strong KIT and phosphorylated KIT expression was detected in the tumour endothelial cells in six (16%) and seven (19%) of the 37 primary glioblastomas examined, respectively. In whole tissue sections, KIT and phosphorylated KIT were expressed in tumour endothelial cells in 13 (59%) and 11 (50%) of the 22 glioblastomas examined, respectively. RNA in situ hybridization showed KIT mRNA expression in most glioblastomas both in tumour vessel endothelial cells and in perinecrotic palisading glioblastoma cells, whereas little KIT mRNA was found in the endothelial cells of colon or pancreatic carcinomas. Phosphorylated KIT, its ligand stem cell factor, and the downstream signalling molecules phosphorylated Akt and mTOR were often expressed in glioblastoma cells located in the perinecrotic tumour areas that often also contained abundant HIF-1alpha. It is concluded that marked KIT and phosphorylated KIT expression is frequently present in the endothelial cells of glioblastomas, which are known to harbour florid microvascular proliferation with characteristic morphological features. Glioblastomas also express phosphorylated KIT and its activated downstream signalling molecules in the tumour cells. Lower levels of KIT and phosphorylated KIT are present in endothelial cells of other tumour types and in normal tissues. Endothelial cell and tumour cell expression of activated KIT might explain in part the responsiveness of glioblastomas to the combination of imatinib (an inhibitor of KIT) and hydroxyurea.
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PMID:Endothelial cell KIT expression in human tumours. 1729 21

The oncogenic epidermal growth factor receptor (EGFR) pathway triggers downstream phosphatidylinositol 3-kinase (PI3K)/RAS-mediated signaling cascades. In transgenic mice, glioblastoma cannot develop on single but only on simultaneous activation of the EGFR signaling mediators RAS and AKT. However, complete blockade of EGFR activation does not result in apoptosis in human glioblastoma cells, suggesting additional cross-talk between downstream pathways. Based on these observations, we investigated combination therapies using protein kinase inhibitors against EGFR, platelet-derived growth factor receptor, and mammalian target of rapamycin, assessing glioblastoma cell survival. Clinically relevant doses of AEE788, Gleevec (imatinib), and RAD001 (everolimus), alone or in combinations, did not induce glioblastoma cell apoptosis. In contrast, simultaneous inactivation of the EGFR downstream targets mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase and PI3K by U0126 and wortmannin triggered rapid tumor cell death. Blocking EGFR with AEE788 in combination with sublethal concentrations of the microtubule stabilizer patupilone also induced apoptosis and reduced cell proliferation in glioblastoma cells, accompanied by reduced AKT and ERK activity. These data underline the critical role of the PI3K/AKT and the RAS/RAF/mitogen-activated protein/ERK kinase/ERK signaling cascades in the cell-intrinsic survival program of sensitive glioblastoma cell lines. We conclude that drug combinations, which down-regulate both ERK and protein kinase B/AKT activity, may prove effective in overcoming cell resistance in a subgroup of glioblastoma.
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PMID:Combination of sublethal concentrations of epidermal growth factor receptor inhibitor and microtubule stabilizer induces apoptosis of glioblastoma cells. 1730 73

The prognosis of patients with glioblastoma, anaplastic astrocytoma, and anaplastic oligodendroglioma remains poor despite standard treatment with radiotherapy and temozolomide. Molecular targeted therapy holds the promise of providing new, more effective treatment options with minimal toxicity. However, the development of targeted therapy for gliomas has been particularly challenging. The oncogenetic process in such tumors is driven by several signaling pathways that are differentially activated or silenced with both parallel and converging complex interactions. Therefore, it has been difficult to identify prevalent targets that act as key promoters of oncogenesis and that can be successfully addressed by novel agents. Several drugs have been tested, including epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (gefitinib and erlotinib), mammalian target of rapamycin (mTOR) inhibitors (temsirolimus and everolimus), and vascular endothelial growth factor receptor (VEGFR), protein kinase C-beta, and other angiogenesis pathways inhibitors (vatalanib, bevacizumab, and enzastaurin). Although preliminary efficacy results of most trials in recurrent disease have fallen short on expectations, substantial advances have been achieved by associated translational research. In this article, we seek to recapitulate the lessons learned in the development of targeted therapy for gliomas, including challenges and pitfalls in the interpretation of preclinical data, specific issues in glioma trial design, insights provided by translational research, changes in paradigms, and future perspectives.
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PMID:Lessons learned in the development of targeted therapy for malignant gliomas. 1762 Apr 23

Glioma has been considered resistant to chemotherapy and radiation. Recently, concomitant and adjuvant chemoradiotherapy with temozolomide has become the standard treatment for newly diagnosed glioblastoma. Conversely (neo-)adjuvant PCV (procarbazine, lomustine, vincristine) failed to improve survival in the more chemoresponsive tumor entities of anaplastic oligoastrocytoma and oligodendroglioma. Preclinical investigations suggest synergism or additivity of radiotherapy and temozolomide in glioma cell lines. Although the relative contribution of the concomitant and the adjuvant chemotherapy, respectively, cannot be assessed, the early introduction of chemotherapy and the simultaneous administration with radiotherapy appear to be key for the improvement of outcome. Epigenetic inactivation of the DNA repair enzyme methylguanine methyltransferase (MGMT) seems to be the strongest predictive marker for outcome in patients treated with alkylating agent chemotherapy. Patients whose tumors do not have MGMT promoter methylation are less likely to benefit from the addition of temozolomide chemotherapy and require alternative treatment strategies. The predictive value of MGMT gene promoter methylation is being validated in ongoing trials aiming at overcoming this resistance by a dose-dense continuous temozolomide administration or in combination with MGMT inhibitors. Understanding of molecular mechanisms allows for rational targeting of specific pathways of repair, signaling, and angiogenesis. The addition of tyrosine kinase inhibitors vatalanib (PTK787) and vandetinib (ZD6474), the integrin inhibitor cilengitide, the monoclonal antibodies bevacizumab and cetuximab, the mammalian target of rapamycin inhibitors temsirolimus and everolimus, and the protein kinase C inhibitor enzastaurin, among other agents, are in clinical investigation, building on the established chemoradiotherapy regimen for newly diagnosed glioblastoma.
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PMID:Chemoradiotherapy in malignant glioma: standard of care and future directions. 1782 63

N(1), N(11)-Diethylnorspermine (DENSPM) is a spermine analog and prototype anti-cancer drug that depletes cellular polyamine, increases cellular oxidative stress through the generation of H(2)O(2) and induces the death of multiple types of cancer cells. However, the survival pathways perturbed by DENSPM are uncertain. To identify these pathways, we examined a series of proteins in the phosphoinositide 3-kinase /AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathways in glioblastoma cell lines before and after treatment with DENSPM. We found that DENSPM did not change the protein levels of PI3K but did reduce the levels of AKT, phosphorylated AKT, mTOR, phosphorylated mTOR, p70(S6K), phosphorylated p70(S6K), 4E-BP1, phosphorylated 4E-BP1 and eIF-4B proteins. From this it appears that DENSPM directly targets the mTOR protein level in these glioblastoma cells by inhibiting mTOR-mediated protein synthesis. Immunofluorescence analysis of mTOR showed that DENSPM sequestered mTOR in the perinuclear region of the cells. We also detected a marked collapse of microtubules in U87 cells and a detachment of cells in a process resembling anoikis. We further showed that the levels of many proteins regulating cell growth and cell adhesion were downregulated, suggesting a broad effect of DENSPM on mTOR-mediated protein synthesis. We conclude that the activation of polyamine catabolism alters the cellular location of mTOR, thus negatively affecting mTOR-mediated protein synthesis and leading to the death of glioblastoma cells.
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PMID:Activation of polyamine catabolism by N1, N11-diethylnorspermine alters the cellular localization of mTOR and downregulates mTOR protein level in glioblastoma cells. 1792 98

The therapeutic goal of cancer treatment has been to trigger tumor-selective cell death. Although cell death can be achieved not only by apoptosis (type I programmed cell death) but also by necrosis, mitotic catastrophe, and autophagy, drugs inducing apoptosis remain the main chemotherapeutic agents in medical oncology. However, cancer cells in their relentless drive to survive, hijack cell processes, resulting in apoptosis resistance, which underlies not only tumorigenesis but also the inherent resistance of certain cancers to radiotherapy and chemotherapy. Unlike apoptosis, which is a caspase-dependent process characterized by nuclear condensation and fragmentation, autophagic cell death is a caspase-independent process characterized by the accumulation of autophagic vacuoles in the cytoplasm accompanied by extensive degradation of the Golgi apparatus, the polyribosomes, and the endoplasmic reticulum, which precedes the destruction of the nucleus. The most striking evidence for proautophagic chemotherapy to overcome apoptosis resistance in cancer cells comes from the use of temozolomide, a proautophagic cytotoxic drug, which has demonstrated real therapeutic benefits in glioblastoma patients and is in clinical trials for several types of apoptosis-resistant cancers. A number of potential common targets in autophagy and apoptosis resistance pathways, that is, mammalian target of rapamycin (mTOR), phosphatidylinositol 3' kinase (PI3K), and Akt have been identified. Thus, further success in certain devastating cancers might be achieved by the combination of proautophagic drugs such as temozolomide with mTOR, PI3K, or Akt inhibitors, or with endoplasmic reticulum stress inhibitors as adjuvant chemotherapies.
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PMID:Proautophagic drugs: a novel means to combat apoptosis-resistant cancers, with a special emphasis on glioblastomas. 1816 16


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