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Author Miranda, A.; Blanco-Prieto, M.; Sousa, J.; Pais, A.; Vitorino, C.
Title Breaching barriers in glioblastoma. Part I: Molecular pathways and novel treatment approaches Type Journal Article
Year (down) 2017 Publication International Journal of Pharmaceutics Abbreviated Journal Int J Pharm
Volume 531 Issue 1 Pages 372-388
Keywords Glioblastoma; Molecular mechanisms; Temozolomide; Therapeutic advances; Therapeutic resistance
Abstract Glioblastoma multiforme (GBM) is the most common primary brain tumour, and the most aggressive in nature. The prognosis for patients with GBM remains poor, with a median survival time of only 1-2 years. The treatment failure relies on the development of resistance by tumour cells and the difficulty of ensuring that drugs effectively cross the dual blood brain barrier/blood brain tumour barrier. The advanced molecular and genetic knowledge has allowed to identify the mechanisms responsible for temozolomide resistance, which represents the standard of care in GBM, along with surgical resection and radiotherapy. Such resistance has motivated the researchers to investigate new avenues for GBM treatment intended to improve patient survival. In this review, we provide an overview of major obstacles to effective treatment of GBM, encompassing biological barriers, cancer stem cells, DNA repair mechanisms, deregulated signalling pathways and autophagy. New insights and potential therapy approaches for GBM are also discussed, emphasizing localized chemotherapy delivered directly to the brain, immunotherapy, gene therapy and nanoparticle-mediated brain drug delivery.
Address Faculty of Pharmacy, University of Coimbra, Portugal; Pharmacometrics Group of the Centre for Neurosciences and Cell Biology (CNC), University of Coimbra, Portugal. Electronic address: csvitorino@ff.uc.pt
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 0378-5173 ISBN Medium
Area Expedition Conference
Notes PMID:28755993 Approved no
Call Number ref @ user @ Serial 96574
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Author Yin, J.; Oh, Y.T.; Kim, J.-Y.; Kim, S.S.; Choi, E.; Kim, T.H.; Hong, J.H.; Chang, N.; Cho, H.J.; Sa, J.K.; Kim, J.C.; Kwon, H.J.; Park, S.; Lin, W.; Nakano, I.; Gwak, H.-S.; Yoo, H.; Lee, S.-H.; Lee, J.; Kim, J.H.; Kim, S.-Y.; Nam, D.-H.; Park, M.-J.; Park, J.B.
Title Transglutaminase 2 Inhibition Reverses Mesenchymal Transdifferentiation of Glioma Stem Cells by Regulating C/EBPbeta Signaling Type Journal Article
Year (down) 2017 Publication Cancer Research Abbreviated Journal Cancer Res
Volume 77 Issue 18 Pages 4973-4984
Keywords
Abstract Necrosis is a hallmark of glioblastoma (GBM) and is responsible for poor prognosis and resistance to conventional therapies. However, the molecular mechanisms underlying necrotic microenvironment-induced malignancy of GBM have not been elucidated. Here, we report that transglutaminase 2 (TGM2) is upregulated in the perinecrotic region of GBM and triggered mesenchymal (MES) transdifferentiation of glioma stem cells (GSC) by regulating master transcription factors (TF), such as C/EBPbeta, TAZ, and STAT3. TGM2 expression was induced by macrophages/microglia-derived cytokines via NF-kappaB activation and further degraded DNA damage-inducible transcript 3 (GADD153) to induce C/EBPbeta expression, resulting in expression of the MES transcriptome. Downregulation of TGM2 decreased sphere-forming ability, tumor size, and radioresistance and survival in a xenograft mouse model through a loss of the MES signature. A TGM2-specific inhibitor GK921 blocked MES transdifferentiation and showed significant therapeutic efficacy in mouse models of GSC. Moreover, TGM2 expression was significantly increased in recurrent MES patients and inversely correlated with patient prognosis. Collectively, our results indicate that TGM2 is a key molecular switch of necrosis-induced MES transdifferentiation and an important therapeutic target for MES GBM. Cancer Res; 77(18); 4973-84. (c)2017 AACR.
Address Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 0008-5472 ISBN Medium
Area Expedition Conference
Notes PMID:28754668 Approved no
Call Number ref @ user @ Serial 96575
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Author Behling, F.; Kaltenstadler, M.; Noell, S.; Schittenhelm, J.; Bender, B.; Eckert, F.; Tabatabai, G.; Tatagiba, M.; Skardelly, M.
Title The Prognostic Impact of Ventricular Opening in Glioblastoma Surgery: A Retrospective Single Center Analysis Type Journal Article
Year (down) 2017 Publication World Neurosurgery Abbreviated Journal World Neurosurg
Volume 106 Issue Pages 615-624
Keywords Extent of resection; Glioblastoma; Hydrocephalus; Overall survival; Prognosis; Tumor volume; Ventricle opening
Abstract OBJECTIVE: Ventricular opening during glioblastoma (GBM) resection is controversial. Sufficient evidence regarding its prognostic role is missing. We investigated the impact of ventricular opening on overall survival (OS), hydrocephalus development, and postoperative morbidity in patients with GBM. METHODS: Patients who underwent primary GBM resection between 2006 and 2013 were assessed retrospectively. Established predictors for overall survival (age, Karnofsky Performance Status, extent of resection, O-6-methylguanine-DNA methyltransferase promoter methylation status, isocitrate dehydrogenase mutation status) and further clinical data (postoperative status, further treatment, preoperative tumor volume, proximity to the ventricle) were included in univariate and multivariate analyses. RESULTS: Thirteen (5.7%) of 229 patients developed a hydrocephalus. Multivariate logistic regression showed that neither ventricular opening, tumor size, proximity to the ventricle, nor extent of resection were significant risk factors for hydrocephalus. Ventricular opening did not delay postoperative therapy and was not associated with neurological morbidity. Kaplan-Meier analysis demonstrated that patients who underwent ventricular opening (n = 114) exhibited a median OS of 14.3 months (12.9-16.5), whereas patients who did not undergo ventricular opening (n = 115) exhibited a median OS of 18.6 months (16.1-20.8). However, multivariate Cox regression (n = 134) did not confirm ventricular opening as an independent negative predictor of OS (risk ratio 1.09, P = 0.77). Instead, it showed that a greater preoperative tumor volume >22.8 cm3 was a negative predictor of OS (risk ratio 1.76, P = 0.02). CONCLUSIONS: Because extent of resection is a strong independent predictor of OS and ventricular opening is safe, neurosurgeons should consider ventricular opening to achieve maximal tumor resection.
Address Department of Neurosurgery, University Hospital Tuebingen, Eberhard Karls University, Tuebingen, Germany; Center for CNS Tumors, Comprehensive Cancer Center Tuebingen Stuttgart, University Hospital Tuebingen, Eberhard Karls University, Tuebingen, Germany
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 1878-8750 ISBN Medium
Area Expedition Conference
Notes PMID:28729143 Approved no
Call Number ref @ user @ Serial 96576
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Author Mercatelli, N.; Galardi, S.; Ciafre, S.A.
Title MicroRNAs as Multifaceted Players in Glioblastoma Multiforme Type Journal Article
Year (down) 2017 Publication International Review of Cell and Molecular Biology Abbreviated Journal Int Rev Cell Mol Biol
Volume 333 Issue Pages 269-323
Keywords Biomarker; Cancer stem cells; Glioblastoma; MicroRNAs; Microenvironment; OncomomiRs; Therapy; Tumor suppressors
Abstract Glioblastoma multiforme (GBM) is the most common and inevitably lethal primary brain tumor, with a median survival rate of only 15 months from diagnosis. The current standard treatment involves maximal surgical resection flanked by radiotherapy and chemotherapy with the alkylating agent temozolomide. However, even such aggressive treatment is never curative, and recurrent tumors always arise, commonly in more aggressive, chemo- and radio-resistant forms, leading to untreatable and deadly tumors. MicroRNAs, recognized major players in cancer, are deeply involved in GBM, as shown by more than a decade of studies. In this review, we revise the main milestones of MicroRNA studies in GBM, and the latest relevant discoveries in this field. Examples are given of MicroRNAs working as “oncomiRs” or tumor suppressors, with specific connections with GBM clinical subtypes, patients' survival, and resistance to therapies. As the interaction of GBM cells with the microenvironment was proven as a key determinant of tumor growth, the role of MicroRNAs in GBM microenvironment, tumor angiogenesis, and tumor-secreted microvesicles is also reviewed. Finally, we discuss the latest findings presenting MicroRNAs as possible therapeutic targets for GBM, or their use as circulating biomarkers in diagnosis and prognosis.
Address Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 1937-6448 ISBN Medium
Area Expedition Conference
Notes PMID:28729027 Approved no
Call Number ref @ user @ Serial 96577
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Author Roh, T.H.; Park, H.H.; Kang, S.-G.; Moon, J.H.; Kim, E.H.; Hong, C.-K.; Ahn, S.S.; Choi, H.J.; Cho, J.; Kim, S.H.; Lee, S.K.; Kim, D.S.; Kim, S.H.; Suh, C.-O.; Lee, K.S.; Chang, J.H.
Title Long-term outcomes of concomitant chemoradiotherapy with temozolomide for newly diagnosed glioblastoma patients: A single-center analysis Type Journal Article
Year (down) 2017 Publication Medicine Abbreviated Journal Medicine (Baltimore)
Volume 96 Issue 27 Pages e7422
Keywords Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating/*therapeutic use; Brain Neoplasms/diagnosis/genetics/metabolism/*therapy; *Chemoradiotherapy; DNA Methylation; DNA Modification Methylases/genetics/metabolism; DNA Repair Enzymes/genetics/metabolism; Dacarbazine/*analogs & derivatives/therapeutic use; Disease-Free Survival; Female; Follow-Up Studies; Glioblastoma/diagnosis/genetics/metabolism/*therapy; Humans; Male; Middle Aged; Prognosis; Promoter Regions, Genetic; Retrospective Studies; Treatment Outcome; Tumor Suppressor Proteins/genetics/metabolism; Young Adult
Abstract The present study analyzed outcomes of surgery followed by concomitant chemoradiotherapy (CCRT) with temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM) at a single institution. Outcomes were retrospectively reviewed in 252 consecutive patients with newly diagnosed GBM who underwent surgery followed by CCRT with TMZ at the authors' institution between 2005 and 2013. At initial operation, 126 (50.0%), 55 (21.8%), 45 (17.9%), and 26 (10.3%) patients underwent gross total resection (GTR), subtotal resection, partial resection (PR), and biopsy, respectively. Their median overall survival (OS) was 20.8 months (95% confidence interval [CI] 17.7-23.9 months) and their median progression-free survival was 12.7 months (95% CI 11.2-14.2 months). The O-methylguanine-DNA methyltransferase (MGMT) promoter was methylated in 78 (34.1%) of the 229 patients assayed, and an isocitrate dehydrogenase 1 mutation was detected in 7 (6.6%) of the 106 patients analyzed. Univariate analyses showed that patient age, involvement of eloquent areas, involvement of the subventricular zone, presence of leptomeningeal seeding, Karnofsky Performance Status, extent of resection (EOR), MGMT promoter methylation, and presence of an oligodendroglioma component were prognostic of OS. Multivariate analysis showed that age, involvement of eloquent areas, presence of leptomeningeal seeding, EOR, and MGMT promoter methylation were significantly predictive of survival. OS in patients with GBM who undergo surgery followed by CCRT with TMZ is enhanced by complete resection. Other factors significantly prognostic of OS include that age, involvement of eloquent areas, presence of leptomeningeal seeding, and MGMT promoter methylation.
Address aYonsei University Graduate School, Seoul bDepartment of Neurosurgery, Ajou University Hospital, Ajou University School of Medicine, Suwon cDepartment of Neurosurgery dDepartment of Radiology eDepartment of Medical Oncology fDepartment of Radiation Oncology gDepartment of Pathology, Yonsei University College of Medicine hBrain Tumor Center, Severance Hospital, Yonsei University Health System iBrain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 0025-7974 ISBN Medium
Area Expedition Conference
Notes PMID:28682902 Approved no
Call Number ref @ user @ Serial 96578
Permanent link to this record