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

Malignant gliomas confer a dismal prognosis. As the molecular events that underlie tumor angiogenesis are elucidated, angiogenesis inhibition is emerging as a promising therapy for recurrent and newly diagnosed tumors. Data from animal studies suggest that angiogenesis inhibition may promote an invasive phenotype in tumor cells. This may represent an important mechanism of resistance to antiangiogenic therapies. Recent studies have begun to clarify the mechanisms by which glioma cells detach from the tumor mass, remodel the extracellular matrix and infiltrate normal brain. An array of potential therapeutic targets exists. Combination therapy with antiangiogenic and novel anti-invasion agents is a promising approach that may produce a synergistic antitumor effect and a survival benefit for patients with these devastating tumors.
 ...
PMID:Inhibition of angiogenesis and invasion in malignant gliomas. 1802 Sep 23

Glioblastoma multiforme (GBM) is the most aggressive form of brain tumor characterized by excessive angiogenesis. The dismal prognosis of patients with GBM warrants the development of new targeting therapies based on novel molecular markers. The EphA2 receptor tyrosine kinase plays a pivotal role in tumor angiogenesis and an increased expression in glioma patients has recently been reported. In this study, we investigated the expression of EphA2 in human normal brain, primary and recurrent GBM and correlated it with clinical pathological parameters and patient's outcome. In addition, intratumor microvascular density was quantified by immunostaining for the endothelial cell marker, von Willebrand factor. A different intensity of the membranous and cytoplastic expression of EphA2 was observed in the 40 primary and recurrent samples of GBM analyzed but not in the normal brain. A high level expression of EphA2 was demonstrated in 24 (60%) of the primary and recurrent GBM analyzed. The increased expression of the EphA2 protein was significantly associated with the adverse outcome of GBM patients (p<0.01 for overall survival). The data presented in this study define the expression pattern of EphA2 in both primary and recurrent glioblastoma and suggest an important role of EphA2 in the pathogenesis of GBM. The EphA2 may be used as a surrogate marker to screen patients for tyrosine kinase inhibitor therapy.
 ...
PMID:Increased expression of EphA2 correlates with adverse outcome in primary and recurrent glioblastoma multiforme patients. 1809 89

Malignant glioma represents one of the most lethal and angiogenic cancers. Angiogenesis is a fundamental process of blood vessel growth that is a hallmark of cancer. Although several molecular mechanisms contribute to tumor angiogenesis in gliomas, the vascular endothelial growth factor (VEGF) pathway appears particularly important and has been a prominent therapeutic target in cancer treatment. Several preclinical studies have demonstrated efficacy of antiangiogenic agents in both subcutaneous and orthotopic malignant glioma xenograft models. Recently, a phase II clinical trial of bevacizumab, a neutralizing monoclonal antibody to VEGF, in combination with irinotecan has demonstrated promising radiographic response and survival benefit in patients with recurrent malignant glioma. Several other antiangiogenic agents such as inhibitors to platelet derived growth factors (PDGFs), fibroblast growth factors (FGFs), angiopoietins/Tie-2 system, protein kinase C and integrins are currently in preclinical and clinical development. Despite the encouraging results of antiangiogenic therapies in malignant glioma, there are several challenges to be overcome to achieve optimal clinical benefit. Identification of biomarkers to predict response or resistance and to monitor antiangiogenic effects is important to enrich for patients who are likely to respond to therapy and to define the optimal biological dose. At present, antiangiogenic therapies remain palliative suggesting that overcoming antiangiogenic resistance may require multi-targeted agents, combination of agents targeting different angiogenic pathways or multi-modality combination with radiation, chemotherapy, other targeted therapeutics or immunotherapy. In this review, we will discuss the current development, promise and challenge of antiangiogenic therapy in malignant glioma.
 ...
PMID:Antiangiogenic therapy in malignant glioma: promise and challenge. 1822 Jul 91

Novel therapies are clearly needed for the treatment of gliomas, and strategies that involve combining oncolytic vectors with chemotherapy hold out significant hope for a more effective treatment of this malignancy. Whether chemotherapy acts directly on tumor cells by inducing cell arrest or cell death, or indirectly by blocking tumor angiogenesis, the resulting delay in tumor growth may provide the oncolytic virus with a wider window of opportunity to overcome the challenge imposed by the growth kinetics of the tumor. In this study we sought to determine whether the oncolytic adenovirus Delta-24-RGD, in combination with everolimus (RAD001), would result in an enhanced anti-glioma effect in vivo. Viability assays showed that Delta-24-RGD antitumoral activity is synergistically enhanced by combination with RAD001. Interestingly, combination treatment of Delta-24-RGD with RAD001 induced autophagy in vitro. We showed that Delta-24-RGD improved survival of tumor-bearing animals in a dose-dependent manner. A significant finding was that RAD001 enhanced the anti-glioma effect of Delta-24-RGD and resulted in the long-term survival of 80% of the experimental animals. Immunostaining of the treated tumors showed upregulation of Atg5, thereby indicating the therapeutic induction of autophagy. This is the first report showing that Delta-24-RGD plus RAD001 causes autophagic cell death, and dramatically increases long-term survival rates of glioma-bearing animals.
 ...
PMID:Delta-24-RGD in combination with RAD001 induces enhanced anti-glioma effect via autophagic cell death. 1825 54

Cannabinoids, the active components of Cannabis sativa L. and their derivatives, inhibit tumor growth in laboratory animals by inducing apoptosis of tumor cells and impairing tumor angiogenesis. It has also been reported that these compounds inhibit tumor cell spreading, but the molecular targets of this cannabinoid action remain elusive. Here, we evaluated the effect of cannabinoids on matrix metalloproteinase (MMP) expression and its effect on tumor cell invasion. Local administration of Delta(9)-tetrahydrocannabinol (THC), the major active ingredient of cannabis, down-regulated MMP-2 expression in gliomas generated in mice, as determined by Western blot, immunofluorescence, and real-time quantitative PCR analyses. This cannabinoid-induced inhibition of MMP-2 expression in gliomas (a) was MMP-2-selective, as levels of other MMP family members were unaffected; (b) was mimicked by JWH-133, a CB(2) cannabinoid receptor-selective agonist that is devoid of psychoactive side effects; (c) was abrogated by fumonisin B1, a selective inhibitor of ceramide biosynthesis; and (d) was also evident in two patients with recurrent glioblastoma multiforme. THC inhibited MMP-2 expression and cell invasion in cultured glioma cells. Manipulation of MMP-2 expression by RNA interference and cDNA overexpression experiments proved that down-regulation of this MMP plays a critical role in THC-mediated inhibition of cell invasion. Cannabinoid-induced inhibition of MMP-2 expression and cell invasion was prevented by blocking ceramide biosynthesis and by knocking-down the expression of the stress protein p8. As MMP-2 up-regulation is associated with high progression and poor prognosis of gliomas and many other tumors, MMP-2 down-regulation constitutes a new hallmark of cannabinoid antitumoral activity.
 ...
PMID:Cannabinoids inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2 expression. 1833 76

Tumstatin - non-collagenous (NC1) domain of the alpha 3 chain of type IV collagen - is a potent inhibitor of tumor angiogenesis. Successful tumor inhibition has been reported in glioma, bronchopulmonary cancer and melanoma experimental model. In this study, the effects of tumstatin, in vitro and in vivo, were investigated in an oral cancer model. Recombinant human tumstatin proteins were obtained by the transformation of Tn 5B1-4 cells, transfected with a plasmid containing tumstatin cDNA using the lipofection method, as previously described. Tumstatin inhibited the proliferation of human umbilical vascular endothelial cells in a dose dependent manner in a proliferation assay. For the in vivo analysis, we established an orthotopic oral squamous cell carcinoma (AT-84 cells) animal (C3H/He) model. In this animal model, the in vivo inhibitory effects of tumstatin on the tumor growth and on the metastasis of tumors were demonstrated. However, the tumors did not show complete remission. Immunostaining of the tumor microvessels (CD-31/PECAM) revealed that the density of tumor microvessels was significantly decreased in the tumstatin treated primary tumors. The results demonstrated that tumstatin delayed the tumor growth and the metastasis of oral squamous cell carcinomas. However, tumstatin alone failed to achieve tumor regression. Therefore, tumstatin might have an adjuvant role in the treatment of oral cancers, in combination with the conventional therapy.
 ...
PMID:Peritumor injections of purified tumstatin delay tumor growth and lymphatic metastasis in an orthotopic oral squamous cell carcinoma model. 1848 94

Vascular basement membrane remodeling is involved in tumor angiogenesis to enable tumor invasion and growth. FT-IR spectral imaging was used to determine changes in tumor blood vessels to reveal protein secondary structure in Rag-gamma immuno-deficient mice sacrificed 14 and 21 days after subcutaneous glioma implantation. For the oldest blood capillaries (diameter >20 microns), tumor growth induced a decrease in triple-helix content (1638 cm(-1); -7.3%; P < 0.05) and an increase in beta turns (1666 and 1615 cm(-1); +4%; P < 0.01). These protein-structure alterations, mainly from type IV collagen, reflected the high angiogenic stress of growing tumors. We propose to use these molecular markers of vascular basement membrane protein alterations for gradation of solid tumors by FT-IR spectral imaging.
 ...
PMID:FT-IR spectral imaging of blood vessels reveals protein secondary structure deviations induced by tumor growth. 1863 46

Malignant gliomas are lethal cancers that display striking cellular heterogeneity. A highly tumorigenic glioma tumor subpopulation, termed cancer stem cells or tumor-initiating cells, promotes therapeutic resistance and tumor angiogenesis. Therefore, targeting cancer stem cells may improve patient survival. We interrogated the role of a neuronal cell adhesion molecule, L1CAM, in glioma stem cells as L1CAM regulates brain development and is expressed in gliomas. L1CAM(+) and CD133(+) cells cosegregated in gliomas, and levels of L1CAM were higher in CD133(+) glioma cells than normal neural progenitors. Targeting L1CAM using lentiviral-mediated short hairpin RNA (shRNA) interference in CD133(+) glioma cells potently disrupted neurosphere formation, induced apoptosis, and inhibited growth specifically in glioma stem cells. We identified a novel mechanism for L1CAM regulation of cell survival as L1CAM knockdown decreased expression of the basic helix-loop-helix transcription factor Olig2 and up-regulated the p21(WAF1/CIP1) tumor suppressor in CD133(+) glioma cells. To determine if targeting L1CAM was sufficient to reduce glioma stem cell tumor growth in vivo, we targeted L1CAM in glioma cells before injection into immunocompromised mice or directly in established tumors. In each glioma xenograft model, shRNA targeting of L1CAM expression in vivo suppressed tumor growth and increased the survival of tumor-bearing animals. Together, these data show that L1CAM is required for maintaining the growth and survival of CD133(+) glioma cells both in vitro and in vivo, and L1CAM may represent a cancer stem cell-specific therapeutic target for improving the treatment of malignant gliomas and other brain tumors.
 ...
PMID:Targeting cancer stem cells through L1CAM suppresses glioma growth. 1867 24

The recombinant kringle domain (UK1) of urokinase-type plasminogen activator (uPA) has been shown to possess anti-angiogenic activity in vitro and in vivo. It has also been found to inhibit in vivo malignant glioma growth. In contrast, direct interaction of the kringle domain of uPA and integrin alphavbeta3 has been reported to be involved in plasminogen and leukocyte activation by uPA. Since integrin alphavbeta3 is involved in tumor angiogenesis, we investigated whether integrin alphavbeta3 is involved in the inhibitory function of UK1 in angiogenesis, by examining its anti-migratory activity. In a modified Boyden chamber assay, the Pichia-expressed UK1 dose-dependently inhibited the VEGF-induced migration of human umbilical vein endothelial cells (HUVECs). However, in the absence of growth factor stimulation, soluble UK1 alone did not induce or inhibit HUVEC migration. In cell adhesion, immobilized UK1 promoted HUVEC adhesion and spreading which were compared to BSA. Pretreatment of the anti-alphavbeta3 integrin antibody, significantly inhibited HUVEC binding to immobilized UK1, whereas neither anti-alpha2beta1 nor anti-alpha5beta1 integrin antibody had any effect, although pre-treatment of the soluble UK1 showed no marked alteration of the binding level of anti-alphavbeta3 antibody to HUVECs in FACS analysis. In a modified Boyden chamber assay, the function blocking antibodies against integrins alphavbeta3, alpha2beta1 and alpha5beta1 did not completely prevent the inhibitory effect of UK1 in HUVEC migration. These results suggest that UK1 interacts with integrin alphavbeta3, but its anti-migratory activity on endothelial cells is not significantly mediated by integrin alphavbeta3.
 ...
PMID:Integrin alphavbeta3 is not significantly implicated in the anti-migratory effect of anti-angiogenic urokinase kringle domain. 1869 16

Growth factor receptors and angiogenesis play major roles in the oncogenesis of gliomas. Over the last several years, several noncytotoxic molecular targeted therapies have been developed against growth factor receptors and tumor angiogenesis. In gliomas, two main anti-growth factor receptor strategies have been evaluated in phase I/II clinical trials: (a) small molecule tyrosine kinase inhibitors (TKIs) and (b) monoclonal antibodies that target growth factors or growth factor receptors other than vascular endothelial growth factor (VEGF). Up to now, few glioma patients have responded to small TKIs (0%-14%) or monoclonal antibodies (three case reports) delivered as a single agent. Greater doses, combined therapies, as well as the identification of molecular biomarkers predictive of response and resistance are important in order to optimize drug delivery and improve efficacy. Antiangiogenic therapies are promising for the treatment of gliomas. Thalidomide and metronomic chemotherapy were the first antiangiogenic strategies evaluated, but they have shown only modest activity. Recent studies of bevacizumab, an anti-VEGF antibody, and irinotecan, a topoisomerase I inhibitor, have demonstrated a high response rate, suggesting that targeted antiangiogenic therapies may play a significant role in the management of high-grade gliomas in the future. However, the toxicity profiles of these agents are not fully defined and the radiological evaluation of possible tumor response is challenging. Clinical evaluation of several VEGF receptor TKIs is currently ongoing; one of these inhibitors, cediranib, has already demonstrated interesting activity as a single agent. The integrin inhibitor cilengitide represents another promising strategy.
 ...
PMID:Therapeutic application of noncytotoxic molecular targeted therapy in gliomas: growth factor receptors and angiogenesis inhibitors. 1877 39


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>