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mgmt glioma

Agm Mostofa, Surendra R Punganuru, Hanumantha Rao Madala, Kalkunte S Srivenugopal
Whether the antimutagenic DNA repair protein MGMT works solo in human cells and if it has other cellular functions is not known. Here, we show that human MGMT associates with PCNA and in turn, with the cell cycle inhibitor, p21cip1 in glioblastoma and other cancer cell lines. MGMT protein was shown to harbor a nearly perfect PCNA-Interacting Protein (PIP box) motif. Isogenic p53-null H1299 cells were engineered to express the p21 protein by two different procedures. Reciprocal immunoprecipitation/western blotting, Far-western blotting, and confocal microscopy confirmed the specific association of MGMT with PCNA and the ability of p21 to strongly disrupt the MGMT-PCNA complexes in tumor cells...
March 2, 2018: Neoplasia: An International Journal for Oncology Research
Chang Shu, Qiong Wang, Xiaoling Yan, Jinhuan Wang
The aim of our study is to build a framework for a better understanding of high-grade glioma (HGG) prognostic-related biomarkers. Whole-genome gene expression microarray was performed to identify differently expressed genes between HGGs and low-grade diffuse gliomas. Several machine learning algorithms were used to filter prognostic-related genes. One hundred ninety-three HGG patients after surgical resection were selected for survival analysis. Immunohistochemistry were performed on these tumor samples to analyze IDH1 mutation status and protein expression of WEE1...
March 3, 2018: Journal of Molecular Neuroscience: MN
Caroline Happold, Nina Stojcheva, Manuela Silginer, Tobias Weiss, Patrick Roth, Guido Reifenberger, Michael Weller
O6 -methylguanine DNA methyltransferase (MGMT) promoter methylation is a predictive biomarker for benefit from alkylating chemotherapy, specifically temozolomide (TMZ), in glioblastoma, the most common malignant intrinsic brain tumor. Glioma-initiating cells (GIC) with stem-like properties have been associated with resistance to therapy and progression. We assessed the levels of MGMT mRNA and MGMT protein by real-time PCR and immunoblot and evaluated the impact of MGMT on TMZ sensitivity in clonogenicity assays in GIC sphere cultures (S) or differentiated adherent monolayer cultures (M)...
February 26, 2018: Journal of Neurochemistry
Tamara Ius, Daniela Cesselli, Miriam Isola, Giovanni Toniato, Giada Pauletto, Giovanni Sciacca, Sara Fabbro, Enrico Pegolo, Simona Rizzato, Antonio Paolo Beltrami, Carla di Loreto, Miran Skrap
PURPOSE OF REVIEW: The purpose of this study was to retrospectively evaluate the use of carmustine wafers (CWs) in the management of high-grade gliomas (HGGs). The data from our monoinstitutional series was compared with studies reported in the literature. Special emphasis was placed on the evaluation of side effects and the analysis of extent of resection and molecular profile as risk factors. RECENT FINDINGS: The implantation of CWs into the resection cavity during HGG treatment to deliver localized chemotherapy, followed by the Stupp protocol, remains debated in a clinical setting, largely due to the lack of appropriate phase III studies...
February 23, 2018: Current Treatment Options in Neurology
Johann-Martin Hempel, Jens Schittenhelm, Uwe Klose, Benjamin Bender, Georg Bier, Marco Skardelly, Ghazaleh Tabatabai, Salvador Castaneda Vega, Ulrike Ernemann, Cornelia Brendle
PURPOSE: To assess the diagnostic performance of dynamic susceptibility contrast perfusion magnetic resonance perfusion imaging (DSC-MRI) for in vivo human glioma molecular profiling. METHODS: In this study 100 patients with histopathologically confirmed glioma who provided written informed consent were retrospectively assessed between January 2016 and February 2017 in two prospective trials that were approved by the local institutional review board. Cerebral blood volume (CBV) measurements from DSC-MRI were assessed, and histogram parameters of relative CBV (rCBV) results were compared among World Health Organization (WHO) 2016 based histological findings and molecular characteristics...
February 21, 2018: Clinical Neuroradiology
Stephanie E Combs, Kerstin A Kessel, Josefine Hesse, Christoph Straube, Claus Zimmer, Friederike Schmidt-Graf, Jürgen Schlegel, Jens Gempt, Bernhard Meyer
BACKGROUND: Generally, re-irradiation (Re-RT) is offered to patients with glioma recurrences with macroscopic lesions. Results are discussed controversially, and some centers postulate limited benefit of Re-RT. Re-RT is generally offered to tumors up to 4 cm in diameter. Re-resection is also discussed controversially; however, recent studies have shown significant benefit. OBJECTIVE: To combine proactive re-resection and early Re-RT in patients with recurrent glioma...
February 16, 2018: Neurosurgery
Christoph Sippl, Steffi Urbschat, Yoo Jin Kim, Sebastian Senger, Joachim Oertel, Ralf Ketter
Promoter methylation of P15, P16, RB transcriptional corepressor 1 (RB1) and O-6-methylguanine-DNA methyltransferase (MGMT) impacts the prognosis of numerous glioma subtypes. However, whether promoter methylation of these genes also has an impact on the clinical course of pilocytic astrocytoma remains unclear. Using methylation-specific polymerase chain reaction, the methylation status of the tumor suppressor genes P15, P16, RB1, and MGMT in pilocytic astrocytomas (n=18) was analyzed. Immunohistochemical staining for the R132H mutation of the isocitrate dehydrogenase (NADP(+)) 1, cytosolic (IDH1) gene was performed...
February 2018: Oncology Letters
Akshitkumar M Mistry, Cindy L Vnencak-Jones, Bret C Mobley
The presence of the single-nucleotide polymorphism (SNP) rs11554137:C>T in the IDH1 gene is associated with a significantly lower survival in acute myeloid leukemia patients. The impact of its presence in glioblastoma on patient survival is unclear. We retrospectively reviewed 171 adult (> 18 years of age) patients treated at a single, tertiary academic center for supratentorial glioblastoma (WHO grade IV) between 2013 and 2017. We conducted Kaplan-Meier overall and progression free survival analyses based on the IDH1 and IDH2 gene status of patients' glioblastoma (IDH wild type, mutant, and IDH1 rs11554137:C>T SNP)...
February 8, 2018: Journal of Neuro-oncology
Lea Kristin Röver, Heidrun Gevensleben, Jörn Dietrich, Friedrich Bootz, Jennifer Landsberg, Diane Goltz, Dimo Dietrich
Immune checkpoints are important targets for immunotherapies. However, knowledge on the epigenetic modification of immune checkpoint genes is sparse. In the present study, we investigated promoter methylation of CTLA4, PD-L1, PD-L2, and PD-1 in diffuse lower-grade gliomas (LGG) harboring isocitrate dehydrogenase (IDH) mutations with regard to mRNA expression levels, clinicopathological parameters, previously established methylation subtypes, immune cell infiltrates, and survival in a cohort of 419 patients with IDH-mutated LGG provided by The Cancer Genome Atlas...
January 24, 2018: EBioMedicine
Riccardo Soffietti, Federica Franchino, Michela Magistrello, Alessia Pellerino, Roberta Rudà
Histopathological typing and grading are the cornerstones of the World Health Organization classification of the central nervous system tumors. It provides clinicians with information on the natural course of the disease and thus guides therapeutic choices. Nonetheless, patients with histologically identical tumors may have different outcomes and response to therapy. In recent years, extensive research has been done on three molecular markers in adult gliomas, namely MGMT promoter methylation, 1p/19q co-deletion, and IDH1/IDH2 mutations...
2018: Progress in Neurological Surgery
Vinay K Puduvalli, Nguyen Hoang
Malignant gliomas have been historically considered unresponsive to chemotherapy due to their intrinsic resistance to conventional anticancer medications and the role of the blood-brain barrier in preventing access of the cytotoxic agents to the tumor. However, recent studies have demonstrated the efficacy of specific drugs in subsets of patients with high-grade astrocytomas that has revived the enthusiasm for the role of systemic chemotherapy against these neoplasms. Temozolomide, a monofunctional alkylator, was the first chemotherapeutic agent to definitively improve survival in adults with newly diagnosed glioblastoma used in combination with radiation therapy with the most pronounced effect being in a subgroup of tumors with MGMT promoter methylation...
2018: Progress in Neurological Surgery
Belinda Kramer, Radhika Singh, Jessica Wischusen, Rebecca Velickovic, Amanda Rush, Shiloh Middlemiss, Yu-Wooi Ching, Ian Edward Alexander, Geoffrey B McCowage
Gene transfer targeting haematopoietic stem cells (HSC) in children has shown sustained therapeutic benefit in the treatment of genetic diseases affecting the immune system, most notably in the severe combined immuno-deficiencies affecting T cell function. The HSC compartment has also been successfully targeted using gene transfer in children with genetic diseases affecting the central nervous system, such as metachromatic leukodystrophy and adrenoleukodystrophy. The HSC is also a target for genetic modification in strategies aiming to confer drug resistance to chemotherapy agents so as to reduce off-target toxicity, and to allow for chemotherapy dose escalation with the possibility of enhanced therapeutic benefit...
January 31, 2018: Human Gene Therapy
Shang-Pen Huang, Yu-Chan Chang, Qie Hua Low, Alexander T H Wu, Chi-Long Chen, Yuan-Feng Lin, Michael Hsiao
There is variation in the survival and therapeutic outcome of patients with glioblastomas (GBMs). Therapy resistance is an important challenge in the treatment of GBM patients. The aim of this study was to identify Temozolomide (TMZ) related genes and confirm their clinical relevance. The TMZ-related genes were discovered by analysis of the gene-expression profiling in our cell-based microarray. Their clinical relevance was verified by in silico meta-analysis of the Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) datasets...
December 26, 2017: Oncotarget
Pierre Bady, Sebastian Kurscheid, Mauro Delorenzi, Thierry Gorlia, Martin J van den Bent, Khê Hoang-Xuan, Élodie Vauléon, Anja Gijtenbeek, Roelien Enting, Brian Thiessen, Olivier Chinot, Frédéric Dhermain, Alba A Brandes, Jaap C Reijneveld, Christine Marosi, Martin J B Taphoorn, Wolfgang Wick, Andreas von Deimling, Pim French, Roger Stupp, Brigitta G Baumert, Monika E Hegi
The optimal treatment for patients with low-grade glioma (LGG) WHO grade II remains controversial. Overall survival ranges from 2 to over 15 years depending on molecular and clinical factors. Hence, risk-adjusted treatments are required for optimizing outcome and quality of life. We aim at identifying mechanisms and associated molecular markers predictive for benefit from radiotherapy (RT) or temozolomide (TMZ) in LGG patients treated in the randomized phase III trial EORTC 22033. As candidate biomarkers for these genotoxic treatments, we considered the DNA methylome of 410 DNA damage response (DDR) genes...
January 24, 2018: Acta Neuropathologica
Costa Emmanuel, Tévi Lawson, Julie Lelotte, Edward Fomekong, Geraldo Vaz, Laurette Renard, Nicolas Whenham, Christian Raftopoulos
BACKGROUND: In spite of aggressive multimodal treatment, survival for patients with glioblastoma (GBM) remains short. Nevertheless, some patients survive much longer than expected and become long- term survival patients. The extent of resection (EoR), Karnofsky Performance Scale (KPS), age and methyl-guanine methyltransferase gene (MGMT) methylation are well-defined prognostic factors, but the characteristics of patients with long-term survival (LTS, survival of at least three years after diagnosis) has not been fully determined yet...
January 23, 2018: Journal of Neurosurgical Sciences
An-An Yin, Nan Lu, Amandine Etcheverry, Marc Aubry, Jill Barnholtz-Sloan, Lu-Hua Zhang, Jean Mosser, Wei Zhang, Xiang Zhang, Yu-He Liu, Ya-Long He
AIMS: We aimed to identify a clinically useful biomarker using DNA methylation-based information to optimize individual treatment of patients with glioblastoma (GBM). METHODS: A six-CpG panel was identified by incorporating genome-wide DNA methylation data and clinical information of three distinct discovery sets and was combined using a risk-score model. Different validation sets of GBMs and lower-grade gliomas and different statistical methods were implemented for prognostic evaluation...
January 19, 2018: CNS Neuroscience & Therapeutics
Sheng-Wei Lai, Bor-Ren Huang, Yu-Shu Liu, Hsiao-Yun Lin, Chun-Chuan Chen, Cheng-Fang Tsai, Dah-Yuu Lu, Chingju Lin
Glioblastoma multiforme (GBM) is the most common type of primary and malignant tumor occurring in the adult central nervous system. Temozolomide (TMZ) has been considered to be one of the most effective chemotherapeutic agents to prolong the survival of patients with glioblastoma. Many glioma cells develop drug-resistance against TMZ that is mediated by increasing O-6-methylguanine-DNA methyltransferase (MGMT) levels. The expression of connexin 43 was increased in the resistant U251 subline compared with the parental U251 cells...
January 2, 2018: International Journal of Molecular Sciences
Tomoko Kurimoto, Akihide Kondo, Ikuko Ogino, Junya Fujimura, Atsushi Arakawa, Hajime Arai, Toshiaki Shimizu
Medulloblastoma is a highly malignant brain tumor that predominately affects children and requires multimodal treatment, including chemotherapy with alkylating agents. O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that plays an important role in tumor resistance to alkylating agents. Recent studies demonstrated that MGMT promoter methylation suppresses the expression of MGMT and is associated with favorable outcomes of malignant glioma patients. However, the MGMT methylation status and its prognostic impact on medulloblastoma have not been fully elucidated to date...
December 2017: Molecular and Clinical Oncology
Yushi Ochiai, Emiko Sano, Yutaka Okamoto, Sodai Yoshimura, Kotaro Makita, Shun Yamamuro, Takashi Ohta, Akiyoshi Ogino, Hisashi Tadakuma, Takuya Ueda, Tomohiro Nakayama, Hiroyuki Hara, Atsuo Yoshino, Yoichi Katayama
Ribavirin, a nucleic acid analog, has been employed as an antiviral agent against RNA and DNA viruses and has become the standard agent used for chronic hepatitis C in combination with interferon-α2a. Furthermore, the potential antitumor efficacy of ribavirin has attracted increasing interest. Recently, we demonstrated a dose-dependent antitumor effect of ribavirin for seven types of malignant glioma cell lines. However, the mechanism underlying the antitumor effect of ribavirin has not yet been fully elucidated...
February 2018: Oncology Reports
Rea D Signorell, Alexandros Papachristodoulou, Jiawen Xiao, Bianca Arpagaus, Tommaso Casalini, Joanes Grandjean, Jana Thamm, Frank Steiniger, Paola Luciani, Davide Brambilla, Beat Werner, Ernst Martin, Michael Weller, Patrick Roth, Jean-Christophe Leroux
Liposomal delivery is a well-established approach to increase the therapeutic index of drugs, mainly in the field of cancer chemotherapy. Here, we report the preparation and characterization of a new liposomal formulation of a derivative of lomeguatrib, a potent O6 -methylguanine-DNA methyltransferase (MGMT) inactivator. The drug had been tested in clinical trials to revert chemoresistance, but was associated with a low therapeutic index. A series of lomeguatrib conjugates with distinct alkyl chain lengths - i...
January 30, 2018: International Journal of Pharmaceutics
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