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targeted therapy for glioblastoma multiforme

Uday B Maachani, Uma Shankavaram, Tamalee Kramp, Philip J Tofilon, Kevin Camphausen, Anita T Tandle
Glioblastoma multiforme (GBM) continues to be the most frequently diagnosed and lethal primary brain tumor. Adjuvant chemo-radiotherapy remains the standard of care following surgical resection. In this study, using reverse phase protein arrays (RPPAs), we assessed the biological effects of radiation on signaling pathways to identify potential radiosensitizing molecular targets. We identified subsets of proteins with clearly concordant/discordant behavior between irradiated and non-irradiated GBM cells in vitro and in vivo...
October 14, 2016: Oncotarget
Amanda L Rinkenbaugh, Patricia C Cogswell, Barbara Calamini, Denise E Dunn, Anders I Persson, William A Weiss, Donald C Lo, Albert S Baldwin
Glioblastoma multiforme (GBM) carries a poor prognosis and continues to lack effective treatments. Glioblastoma stem cells (GSCs) drive tumor formation, invasion, and drug resistance and, as such, are the focus of studies to identify new therapies for disease control. Here, we identify the involvement of IKK and NF-κB signaling in the maintenance of GSCs. Inhibition of this pathway impairs self-renewal as analyzed in tumorsphere formation and GBM expansion as analyzed in brain slice culture. Interestingly, both the canonical and non-canonical branches of the NF-κB pathway are shown to contribute to this phenotype...
October 6, 2016: Oncotarget
Bo Ram Kang, Seung-Hoon Yang, Bo-Ryehn Chung, Woong Kim, YoungSoo Kim
High-grade glioma is a highly malignant and metastatic brain cancer, resistant to many existing anticancer treatments. In such glioma cancer cells, the glucose-regulated protein 78 kDa (GRP78) is particularly highly up-regulated. Former studies have thus targeted mutation-free GRP78 not only to detect glioma cancer cells specifically but also to enhance cytotoxic effect. We focus on cell surface-expressed GRP78 as a target for suppressing high-grade glioma cell lines. Glioblastoma multiforme (GBM) cell line, highly malignant glioma cells, was first injected into 5-week-old athymic mice to confirm and compare GRP78 expression in vivo in xenografted and normal brain tissue...
October 7, 2016: Scientific Reports
Martin J Hicks, Maria J Chiuchiolo, Douglas Ballon, Jonathan P Dyke, Eric Aronowitz, Kosuke Funato, Viviane Tabar, David Havlicek, Fan Fan, Dolan Sondhi, Stephen M Kaminsky, Ronald G Crystal
Glioblastoma multiforme (GBM) is the most common and aggressive primary intracranial brain tumor in adults with a mean survival of 14 to 15 months. Aberrant activation of the epidermal growth factor receptor (EGFR) plays a significant role in GBM progression, with amplification or overexpression of EGFR in 60% of GBM tumors. To target EGFR expressed by GBM, we have developed a strategy to deliver the coding sequence for cetuximab, an anti-EGFR antibody, directly to the CNS using an adeno-associated virus serotype rh...
2016: PloS One
Wen-Juan Huang, Wei-Wei Chen, Xia Zhang
Central nervous system-based cancers have a much higher mortality rate with the 2016 estimates at 6.4 for incidence and 4.3 for deaths per 100,000 individuals. Grade IV astrocytomas, known as glioblastomas are highly aggressive and show a high proliferation index, diffused infiltration, angiogenesis, microvascular proliferation and pleomorphic vessels, resistance to apoptosis, and pseudopalisading necrosis. Extensive hypoxic regions in glioblastomas contribute to the highly malignant phenotype of these tumors...
October 2016: Oncology Letters
Jiange Qiu, Zhi Shi, Jianxiong Jiang
Glioblastoma multiforme (GBM) represents the most prevalent brain primary tumor, yet there is a lack of effective treatment. With current therapies, fewer than 5% of patients with GBM survive more than 5 years after diagnosis. Mounting evidence from epidemiological studies reveals that the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) is correlated with reduced incidence of GBM, suggesting that cyclooxygenase-2 (COX-2) and its major product within the brain, prostaglandin E2 (PGE2), are involved in the development and progression of GBM...
September 28, 2016: Drug Discovery Today
Claudia R Oliva, Tahireh Markert, Larry J Ross, E Lucile White, Lynn Rasmussen, Wei Zhang, Maaike Everts, Douglas R Moellering, Shannon M Bailey, Mark J Suto, Corinne E Griguer
The enzyme cytochrome c oxidase (CcO), or complex IV (EC, is a large transmembrane protein complex that serves as the last enzyme in the respiratory electron transport chain of eukaryotic mitochondria. CcO promotes the switch from glycolytic to oxidative phosphorylation (OXPHOS) metabolism and has been associated with increased self-renewal characteristics in gliomas. Increased CcO activity in tumors has been associated with tumor progression after chemotherapy failure, and patients with primary glioblastoma multiforme and high tumor CcO activity have worse clinical outcomes than those with low tumor CcO activity...
September 27, 2016: Journal of Biological Chemistry
Haiqian Liang, Renjie Wang, Ying Jin, Jianwei Li, Sai Zhang
Although surgical treatment, chemotherapy, and radiotherapy have improved the overall survival rate in glioblastoma multiforme (GBM), further intensive research of GBM's molecular mechanism is still needed. In this study, we observed that miR-422a was downregulated in GBM tissues and cell lines by quantitative real-time polymerase chain reaction (PCR) and primer extension assay. Overexpression of miR-422a significantly reduced the cell proliferation, migration, and invasion of GBM cells. Functional study indicated that miR-422a inhibited cell proliferation, invasion, and migration by targeting PIK3CA, an important member of PI3K/Akt signal pathway...
2016: American Journal of Cancer Research
Amanda L Edwards, Dimphna H Meijer, Rachel M Guerra, Remco J Molenaar, John A Alberta, Federico Bernal, Gregory H Bird, Charles D Stiles, Loren D Walensky
Basic helix-loop-helix (bHLH) transcription factors play critical roles in organism development and disease by regulating cell proliferation and differentiation. Transcriptional activity, whether by bHLH homo- or heterodimerization, is dependent on protein-protein and protein-DNA interactions mediated by α-helices. Thus, α-helical decoys have been proposed as potential targeted therapies for pathologic bHLH transcription. Here, we developed a library of stabilized α-helices of OLIG2 (SAH-OLIG2) to test the capacity of hydrocarbon-stapled peptides to disrupt OLIG2 homodimerization, which drives the development and chemoresistance of glioblastoma multiforme, one of the deadliest forms of human brain cancer...
October 4, 2016: ACS Chemical Biology
Leiming Zhang, Junlin Ren, Hangyu Zhang, Gang Cheng, Yanming Xu, Shuangwu Yang, Chao Dong, Dandong Fang, Jianning Zhang, Angang Yang
Glioblastoma multiforme (GBM), which is associated with a high rate of morbidity and mortality, is among the most malignant and treatment-refractory neoplasms in human adults. As GBM is highly resistant to conventional therapies, immunotherapies are a promising treatment candidate. HER2 is an attractive target for GBM immunotherapy, as its expression is highly associated with various types of GBM. We previously reported that a novel HER2-targeted recombinant protein e23sFv-Fdt-casp6 has an antitumor effect on HER2-positive gastric cancer cells...
September 12, 2016: Oncology Reports
Christos Yapijakis, Maria Adamopoulou, Konstantina Tasiouka, Costas Voumvourakis, George Stranjalis
BACKGROUND/AIM: A deeper understanding of the complex molecular pathology of brain malignancies is needed in order to develop more effective and targeted therapies of these highly lethal disorders. In an effort to further enlighten the molecular pathology of brain oncogenesis involving the her-2 (erbB-2/neu/ngl)/N-ras/nf1 pathway, we screened the genotypes of specimens from various types of brain tumors. MATERIALS AND METHODS: The studied specimens included 35 biopsies of four general categories: 13 neuroglial tumors (4 astrocytomas, 2 oligodendrogliomas, 7 glioblastomas multiforme), 14 meningiomas, 3 other nervous system tumors (2 schwannomas, 1 craniopharyngioma) and 5 metastatic tumors (such as lung carcinomas and chronic myelocytic leukemia)...
September 2016: Anticancer Research
E Cosset, T Petty, V Dutoit, D Tirefort, P Otten-Hernandez, L Farinelli, P-Y Dietrich, O Preynat-Seauve
Glioblastoma multiforme (GBM) is among the most aggressive cancers associated with massive infiltration of peritumoral parenchyma by migrating tumor cells. The infiltrative nature of GBM cells, the intratumoral heterogeneity concomitant with redundant signaling pathways likely underlie the inability of conventional and targeted therapies to achieve long-term remissions. In this respect, microRNAs (miRNAs), which are endogenous small non-coding RNAs that play a role in cancer aggressiveness, emerge as possible relevant prognostic biomarkers or therapeutic targets for treatment of malignant gliomas...
November 2016: Biomaterials
Zohar Shatsberg, Xuejiao Zhang, Paula Ofek, Shashwat Malhotra, Adva Krivitsky, Anna Scomparin, Galia Tiram, Marcelo Calderón, Rainer Haag, Ronit Satchi-Fainaro
Glioblastoma Multiforme (GBM) is one of the most aggressive forms of all cancers. The median survival with current standard-of-care radiation and chemotherapy is about 14months. GBM is difficult to treat due to heterogeneity in cancer cell population. MicroRNA-based drugs have rapidly become a vast and burgeoning field due to the ability of a microRNA (miRNA) to target many genes involved in key cellular pathways. However, in vivo delivery of miRNA remains a crucial challenge for its therapeutic success. To bypass this shortcoming, we designed polymeric nanogels (NGs), which are based on a polyglycerol-scaffold, as a new strategy of miRNA delivery for GBM therapy...
October 10, 2016: Journal of Controlled Release: Official Journal of the Controlled Release Society
Rekha Jain, Apurva Atak, Avani Yeola, Sanjeeva Srivastava
: Glioblastoma multiforme is Grade IV brain tumor associated with high mortality and limited therapeutics. Signal Transducer and Activator of Transcription 3 (STAT3) is persistently active in several cancers including gliomas, and plays a major role in disease progression and survival of glioma patients, thus being a potential therapeutic target for treatment. S3I201 and its analogs inhibit the transcriptional functions of STAT3 and reduce growth of tumor tissues. Here we have studied proteomic alteration associated with S3I201 treated U87 cells using 2-DE and Isobaric tags for relative and absolute quantitation coupled with mass spectrometry...
August 23, 2016: Journal of Proteomics
Gang Wang, Xing-Li Fu, Jun-Jie Wang, Rui Guan, Xiang-Jun Tang
Glioblastoma multiforme is a common primary brain tumor, which exhibits an imbalance between glioma cell growth and glucose metabolism. Recent discoveries have found the multiple pathways and downstream genes are involved in the dysregulated metabolic pathway allows tumor to start and progress, which is critical to the patients with glioblastoma associated with significant systemic and immunosuppression. Moreover, immune microenvironment is considered a major obstacle to generating an effective antitumor immune response...
May 12, 2016: Current Cancer Drug Targets
Jiwei Wang, Qichao Qi, Zichao Feng, Xin Zhang, Bin Huang, Anjing Chen, Lars Prestegarden, Xingang Li, Jian Wang
There is an urgent need for new therapeutic strategies for patients with glioblastoma multiforme (GBM). Previous studies have shown that berberine (BBR), a natural plant alkaloid, has potent anti-tumor activity. However, the mechanisms leading to cancer cell death have not been clearly elucidated. In this study, we show that BBR has profound effects on the metabolic state of GBM cells, leading to high autophagy flux and impaired glycolytic capacity. Functionally, these alterations reduce the invasive properties, proliferative potential and induce apoptotic cell death...
August 19, 2016: Oncotarget
Ilya V Ulasov, Natalya V Kaverina, Dhimankrishna Ghosh, Marya A Baryshnikova, Zaira G Kadagidze, Apollon I Karseladze, Anatoly Y Baryshnikov, Charles S Cobbs
Glioblastoma multiforme (GBM) is a rapidly progressive brain tumor with a median survival of 15-19 months. Therapeutic resistance and recurrence of the disease is attributed to cancer stem cells (CSC). Here, we report that CMV70-3P miRNA encoded by CMV increases GBM CSC stemness. Inhibition of CMV70-3P expression using oligo inhibitors significantly attenuated the ability of primary glioma cells to proliferate and form neurospheres. At the molecular level, we show that CM70-3P increases expression of cellular SOX2...
August 10, 2016: Oncotarget
Marianna Colamaio, Nadia Tosti, Francesca Puca, Alessia Mari, Rosaria Gattordo, Yalçın Kuzay, Antonella Federico, Anna Pepe, Daniela Sarnataro, Elvira Ragozzino, Maddalena Raia, Hidenari Hirata, Marica Gemei, Koshi Mimori, Luigi Del Vecchio, Sabrina Battista, Alfredo Fusco
OBJECTIVE: Glioblastoma multiforme (GBM) develops from a small subpopulation of stem-like cells, which are endowed with the ability to self-renew, proliferate and give rise to progeny of multiple neuroepithelial lineages. These cells are resistant to conventional chemo- and radiotherapy and are hence also responsible for tumor recurrence. HMGA1 overexpression has been shown to correlate with proliferation, invasion, and angiogenesis of GBMs and to affect self-renewal of cancer stem cells from colon cancer...
October 2016: Expert Opinion on Therapeutic Targets
Sarmistha Talukdar, Swadesh K Das, Anjan K Pradhan, Luni Emdad, Xue-Ning Shen, Jolene J Windle, Devanand Sarkar, Paul B Fisher
Glioblastoma multiforme (GBM) is an aggressive cancer with current therapies only marginally impacting on patient survival. Glioma stem cells (GSCs), a subpopulation of highly tumorigenic cells, are considered major contributors to glioma progression and play seminal roles in therapy resistance, immune evasion and increased invasion. Despite clinical relevance, effective/selective therapeutic targeting strategies for GSCs do not exist, potentially due to the lack of a definitive understanding of key regulators of GSCs...
July 26, 2016: Oncotarget
Ulrich Jarry, Cynthia Chauvin, Noémie Joalland, Alexandra Léger, Sandrine Minault, Myriam Robard, Marc Bonneville, Lisa Oliver, François M Vallette, Henri Vié, Claire Pecqueur, Emmanuel Scotet
Glioblastoma multiforme (GBM) represents the most frequent and deadliest primary brain tumor. Aggressive treatment still fails to eliminate deep brain infiltrative and highly resistant tumor cells. Human Vγ9Vδ2 T cells, the major peripheral blood γδ T cell subset, react against a wide array of tumor cells and represent attractive immune effector T cells for the design of antitumor therapies. This study aims at providing a preclinical rationale for immunotherapies in GBM based on stereotaxic administration of allogeneic human Vγ9Vδ2 T cells...
June 2016: Oncoimmunology
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