Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Viruses have adapted through millennia of evolution to effectively invade and lyse cells through diverse mechanisms. Strains of the attenuated measles virus Edmonston (MV-Edm) vaccine lineage can preferentially infect and destroy cancerous cells while sparing the surrounding tissues. This specificity is predominantly due to overexpression of the measles virus receptor CD46 in tumor cells. To facilitate in vivo monitoring of viral gene expression and replication, these oncolytic strains have been engineered to either express soluble marker peptides, such as the human carcinoembryonic antigen (CEA; MV-CEA virus), or genes that facilitate imaging and therapy, such as the human thyroidal sodium iodide symporter (NIS) gene (MV-NIS). Preclinical efficacy and safety data for engineered oncolytic MV-Edm derivatives that led to their clinical translation are discussed in this review, and an overview of the early experience in three ongoing clinical trials of patients with ovarian cancer, glioblastoma multiforme and multiple myeloma is provided. The information obtained from these ongoing trials will guide the future clinical application and further development of MV strains as anticancer agents.
Curr Opin Mol Ther 2009 Feb
PMID:Clinical testing of engineered oncolytic measles virus strains in the treatment of cancer: an overview. 1916 59

A commonly activated signaling cascade in many human malignancies, including glioblastoma multiforme, is the Akt pathway. This pathway can be activated via numerous upstream alterations including genomic amplification of epidermal growth factor receptor, PTEN deletion, or PIK3CA mutations. In this study, we screened phosphatidylinositol 3-kinase/Akt small-molecule inhibitors in an isogenic cell culture system with an activated Akt pathway secondary to a PIK3CA mutation. One small molecule, A-443654, showed the greatest selective inhibition of cells with the mutant phenotype. Based on these findings, this inhibitor was screened in vitro against a panel of glioblastoma multiforme cell lines. All cell lines tested were sensitive to A-443654 with a mean IC(50) of approximately 150 nmol/L. An analogue of A-443654, methylated at a region that blocks Akt binding, was on average 36-fold less active. Caspase assays and dual flow cytometric analysis showed an apoptotic mechanism of cell death. A-443654 was further tested in a rat intracranial model of glioblastoma multiforme. Animals treated intracranially with polymers containing A-443654 had significantly extended survival compared with control animals; animals survived 79% and 43% longer than controls when A-443654-containing polymers were implanted simultaneously or in a delayed fashion, respectively. This small molecule also inhibited glioblastoma multiforme stem-like cells with similar efficacy compared with traditionally cultured glioblastoma multiforme cell lines. These results suggest that local delivery of an Akt small-molecule inhibitor is effective against experimental intracranial glioma, with no observed resistance to glioblastoma multiforme cells grown in stem cell conditions.
Mol Cancer Ther 2009 Feb
PMID:Inhibition of Akt inhibits growth of glioblastoma and glioblastoma stem-like cells. 1920 28

Glioblastoma multiforme (GBM) represents an extremely chemoresistant tumour type. Here, authors analysed the immunophenotype of GBM tumours by flow cytometry and correlated the immunophenotypic characteristics with sensitivity to chemotherapy. The expression of selected neural and non-neural differentiation markers including A2B5, CD34, CD45, CD56, CD117, CD133, EGFR, GFAP, Her-2/neu, LIFR, nestin, NGFR, Pgp and vimentin was analysed by flow cytometry in eleven GBM (WHO gr.IV) patients. The sensitivity of tumour cells to a panel of chemotherapeutic agents was tested by the MTT assay. All tumours were positive for A2B5, CD56, nestin and vimentin. CD133, EGFR, LIFR, NGFR and Pgp were expressed only by minor tumour cell subpopulations. CD34, CD45, CD117, GFAP and Her-2/neu were constantly negative. Direct correlations were found between the immunophenotypic markers and chemosensitivity: A2B5 vs lomustine (r(2) = 0.642, P = 0.033), CD56 vs cisplatin (r(2) = 0.745, P = 0.013), %Pgp(+) vs vincristine (r(2) = 0.846, P = 0.008), and %NGFR(+) vs daunorubicine (r(2) = 0.672, P = 0.047) and topotecan (r(2) = 0.792, P = 0.011). In contrast, inverse correlations were observed between: EGFR vs paclitaxel (r(2) = -0.676, P = 0.046), CD133 vs dacarbazine (r(2) = -0.636, P = 0.048) and LIFR vs daunorubicine (r(2) = -0.878, P = 0.004). Finally, significant associations were also found among sensitivities to different chemotherapeutic agents and among different immunophenotypic markers. In conclusion, histopathologically identical GBM tumours displayed a marked immunophenotypic heterogeneity. The expression of A2B5, CD56, NGFR and Pgp appeared to be associated with chemoresistance whereas CD133, EGFR and LIFR expression was characteristic of chemosensitive tumours. We suggest that flow cytometric imunophenotypic analysis of GBM may predict chemoresponsiveness and help to identify patients who could potentially benefit from chemotherapy.
Cell Mol Neurobiol 2009 Sep
PMID:Flow cytometry analysis of neural differentiation markers expression in human glioblastomas may predict their response to chemotherapy. 1928 88

Amorphous aggregation is a major problem for protein biopharmaceuticals, and aggregate formation in a drug formulation can have serious health implications for the patient. In many cases, an immunogenic response is generated from the administration of a drug product containing aggregated protein. This becomes especially significant when the patient requires long-term or repeated administration of the drug, because the likelihood of a severe immune response increases. While the prevention of protein aggregation is critically important for the future of protein pharmaceuticals, the mechanism of amorphous aggregation is still poorly understood. The lack of understanding regarding nonfibrillar aggregation is largely due to the fact that assembly is difficult to study. In particular the role that various structural features (i.e., alpha-helix, beta-structure, disulfide bonds) play in the aggregation process varies with the amino acid sequence and is dependent upon tertiary structure and solution conditions. Well-structured proteins do not readily aggregate in solution, whereas partially unfolded proteins tend to aggregate rapidly and often become insoluble. Here, we present a unique and simple system for studying amorphous protein aggregation. We have previously reported the isolation of the basic leucine zipper (bZIP) domain of activating transcription factor 5 (ATF5), a protein notable for its potential as a pharmaceutical target for treatment of glioblastoma multiforme. This domain consists of a single alpha-helix and possesses a single cysteine residue. It is only partially structured and displays marginal stability in solution under physiological conditions. We have modulated solution conditions that affect backbone solubility and the oxidation state of the thiol to successfully investigate the role that alpha-helical structure and disulfide bond formation play in protein stability. Our data indicate that covalent cross-linking helps to retain ATF5's helicity, which inhibits the formation of large aggregates. These studies have led to the identification of stabilizing conditions for ATF5, which will enable further study of the protein as a pharmaceutical target. Moreover, this work has general implications for analyzing stability of helical proteins in vitro as well as the specific atomic-level interactions in ATF5 that contribute to instability and self-association.
Mol Pharm
PMID:Effects of disulfide bond formation and protein helicity on the aggregation of activating transcription factor 5. 1943 74

Glioblastoma multiforme (GBM) is an extremely malignant brain tumor. To identify new genomic alterations in GBM, genomic DNA of tumor tissue/explants from 55 individuals and 6 GBM cell lines were examined using single nucleotide polymorphism DNA microarray (SNP-Chip). Further gene expression analysis relied on an additional 56 GBM samples. SNP-Chip results were validated using several techniques, including quantitative PCR (Q-PCR), nucleotide sequencing, and a combination of Q-PCR and detection of microsatellite markers for loss of heterozygosity with normal copy number [acquired uniparental disomy (AUPD)]. Whole genomic DNA copy number in each GBM sample was profiled by SNP-Chip. Several signaling pathways were frequently abnormal. Either the p16(INK4A)/p15(INK4B)-CDK4/6-pRb or p14(ARF)-MDM2/4-p53 pathways were abnormal in 89% (49 of 55) of cases. Simultaneous abnormalities of both pathways occurred in 84% (46 of 55) samples. The phosphoinositide 3-kinase pathway was altered in 71% (39 of 55) GBMs either by deletion of PTEN or amplification of epidermal growth factor receptor and/or vascular endothelial growth factor receptor/platelet-derived growth factor receptor alpha. Deletion of chromosome 6q26-27 often occurred (16 of 55 samples). The minimum common deleted region included PARK2, PACRG, QKI, and PDE10A genes. Further reverse transcription Q-PCR studies showed that PARK2 expression was decreased in another collection of GBMs at a frequency of 61% (34 of 56) of samples. The 1p36.23 region was deleted in 35% (19 of 55) of samples. Notably, three samples had homozygous deletion encompassing this site. Also, a novel internal deletion of a putative tumor suppressor gene, LRP1B, was discovered causing an aberrant protein. AUPDs occurred in 58% (32 of 55) of the GBM samples and five of six GBM cell lines. A common AUPD was found at chromosome 17p13.3-12 (included p53 gene) in 13 of 61 samples and cell lines. Single-strand conformational polymorphism and nucleotide sequencing showed that 9 of 13 of these samples had homozygous p53 mutations, suggesting that mitotic recombination duplicated the abnormal p53 gene, probably providing a growth advantage to these cells. A significantly shortened survival time was found in patients with 13q14 (RB) deletion or 17p13.1 (p53) deletion/AUPD. Taken together, these results suggest that this technique is a rapid, robust, and inexpensive method to profile genome-wide abnormalities in GBM.
Mol Cancer Res 2009 May
PMID:High-resolution genomic copy number profiling of glioblastoma multiforme by single nucleotide polymorphism DNA microarray. 1943 19

Cell motility and resistance to apoptosis characterize glioblastoma multiforme growth and malignancy. Narciclasine, a plant growth modulator, could represent a powerful new weapon targeting the Achilles' heel of glioblastoma multiforme and may offer the potential to better combat these devastating malignancies. The in vitro effects of narciclasine on cell proliferation, morphology, actin cytoskeleton organization, and the Rho/Rho kinase/LIM kinase/cofilin pathway and its antitumor activity in vivo have been determined in models of human glioblastoma multiforme. Narciclasine impairs glioblastoma multiforme growth by markedly decreasing mitotic rates without inducing apoptosis. The compound also modulates the Rho/Rho kinase/LIM kinase/cofilin signaling pathway, greatly increasing GTPase RhoA activity as well as inducing actin stress fiber formation in a RhoA-dependent manner. Lastly, the treatment of human glioblastoma multiforme orthotopic xenograft- bearing mice with nontoxic doses of narciclasine significantly increased their survival. Narciclasine antitumor effects were of the same magnitude as those of temozolomide, the drug associated with the highest therapeutic benefits in treating glioblastoma multiforme patients. Our results show for the first time that narciclasine, a plant growth modulator, activates Rho and stress fibers in glioblastoma multiforme cells and significantly increases the survival of human glioblastoma multiforme preclinical models. This statement is made despite the recognition that to date, irrespective of treatment, no single glioblastoma multiforme patient has been cured.
Mol Cancer Ther 2009 Jul
PMID:Narciclasine, a plant growth modulator, activates Rho and stress fibers in glioblastoma cells. 1953 73

Glioblastoma multiforme (GBM) can arise de novo or progress from a lower to higher grade and can possess a series of genetic alterations and dynamic progressions, which have been correlated with the molecular pathology of GBM. Epidermal growth factor receptor (EGFR) has been shown to be overexpressed in a variety of tumors and is one of the important mediators responsible for the development of high-grade gliomas, especially in primary glioblastomas. Most recently, RNA interference (RNAi), in which double-stranded RNA (dsRNA) induces sequence-specific degradation of the targeting messenger RNA (mRNA), has been extensively developed and studied. RNAi is able to silence the targeted gene expression more efficiently and specifically. In the present study, we silence the EGFR expression using two separate short interfering RNAs (siRNAs) targeting the extracellular ligand-binding domain and intracellular tyrosine kinase domain, respectively. We demonstrate that suppression of EGFR expression, by using either antisense or siRNA approaches, inhibits U251 glioblastoma cell growth in vitro and in vivo, and siRNA seems to be more effective than the antisense approach.
Methods Mol Biol 2009
PMID:Silencing epidermal growth factor receptor by RNA interference in glioma. 1956 11

We performed a clinical trial of gene therapy in patients with recurrent glioblastoma multiforme based on retroviral vector-mediated combined delivery of interleukin-2 and thymidine kinase of herpes simplex virus (HSV)-1. Treatment consisted of intratumor injection of retroviral vector-producing cells, followed by intravenous ganciclovir administration. The primary endpoints of the study were the evaluation of the safety of the treatment and demonstration of transduction of tumor cells. Here, we report details on the clinical protocol and the methods used.
Methods Mol Biol 2009
PMID:HSV-TK/IL-2 gene therapy for glioblastoma multiforme. 1956 21

Accumulating evidence suggests that only a fraction of neoplastic cells, defined as cancer stem cells (CSC), are responsible for tumor perpetuation. Recent data suggest that neurospheres (NS) from glioblastoma multiforme (GBM) are enriched in CSC. The characterization of this subpopulation of brain tumor cells with a potent tumorigenic activity supports the cancer stem cell hypothesis in solid tumors and may imply that cancer cells are differentially targeted by treatments, including dendritic cell (DC) immunotherapy. To test therapeutic strategies, a good model mimicking the characteristics of GBM-NS and GBM-AC (Adherent Cells) was necessary. One of the most frequently used murine brain tumor models is the GL261 glioma cell line. To see whether GL261 cells could mimic the growth of human GBM-CSC we let them grow in EGF/bFGF without serum. After 5 days neurospheres were visible in the culture medium and were proliferating continuously. The characterization in vivo and in vitro demonstrates that GL261-NS satisfy criteria used to identify CSC and are more immunogenic than AC. DC loaded with GL261-NS lysates protect mice against tumors from both GL261-NS and GL261-AC. Our results suggest that only DC vaccination against neurospheres can restrain the growth of a highly infiltrating and aggressive model of glioma and may have implications for the design of novel, more effective immunotherapy trials for malignant glioma and possibly other malignancies.
Methods Mol Biol 2009
PMID:Dendritic cell vaccines for cancer stem cells. 1958 31

Glioblastoma multiforme (GBM) are the most common primary brain tumor and are resistant to standard therapies. The nondividing nature of normal brain provides an opportunity to enhance the therapeutic ratio by combining radiation with inhibitors of replication-specific DNA repair pathways. Based on our previous findings that inhibition of poly(ADP-ribose) polymerase (PARP) increases radiosensitivity of human glioma cells in a replication-dependent manner and generates excess DNA breaks that are repaired by homologous recombination (HR), we hypothesized that inhibition of HR would amplify the replication-specific radiosensitizing effects of PARP inhibition. Specific inhibitors of HR are not available, but the heat shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) has been reported to inhibit HR function. The radiosensitizing effects of 17-AAG and the PARP inhibitor olaparib were assessed, and the underlying mechanisms explored. 17-AAG down-regulated Rad51 and BRCA2 protein levels, abrogated induction of Rad51 foci by radiation, and inhibited HR measured by the I-Sce1 assay. Individually, 17-AAG and olaparib had modest, replication-dependent radiosensitizing effects on T98G glioma cells. Additive radiosensitization was observed with combination treatment, mirrored by increases in gammaH2AX foci in G(2)-phase cells. Unlike olaparib, 17-AAG did not increase radiation sensitivity of Chinese hamster ovary cells, indicating tumor specificity. However, 17-AAG also enhanced radiosensitivity in HR-deficient cells, indicating that its effects were only partially mediated by HR inhibition. Additional mechanisms are likely to include destabilization of oncoproteins that are up-regulated in GBM. 17-AAG is therefore a tumor-specific, replication-dependent radiosensitizer that enhances the effects of PARP inhibition. This combination has therapeutic potential in the management of GBM.
Mol Cancer Ther 2009 Aug
PMID:Enhanced radiosensitization of human glioma cells by combining inhibition of poly(ADP-ribose) polymerase with inhibition of heat shock protein 90. 1967 36


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