Current and Future Trends on Diagnosis and Prognosis of Glioblastoma: From Molecular Biology to Proteomics

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Abstract

Glioblastoma multiforme is the most aggressive malignant tumor of the central nervous system. Due to the absence of effective pharmacological and surgical treatments, the identification of early diagnostic and prognostic biomarkers is of key importance to improve the survival rate of patients and to develop new personalized treatments. On these bases, the aim of this review article is to summarize the current knowledge regarding the application of molecular biology and proteomics techniques for the identification of novel biomarkers through the analysis of different biological samples obtained from glioblastoma patients, including DNA, microRNAs, proteins, small molecules, circulating tumor cells, extracellular vesicles, etc. Both benefits and pitfalls of molecular biology and proteomics analyses are discussed, including the different mass spectrometry-based analytical techniques, highlighting how these investigation strategies are powerful tools to study the biology of glioblastoma, as well as to develop advanced methods for the management of this pathology.

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Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity.

Monika E Hegi, Lili Liu, James G. Herman … (2008)

Resistance to alkylating agents via direct DNA repair by O(6)-methylguanine methyltransferase (MGMT) remains a significant barrier to the successful treatment of patients with malignant glioma. The relative expression of MGMT in the tumor may determine response to alkylating agents, and epigenetic silencing of the MGMT gene by promoter methylation plays an important role in regulating MGMT expression in gliomas. MGMT promoter methylation is correlated with improved progression-free and overall survival in patients treated with alkylating agents. Strategies to overcome MGMT-mediated chemoresistance are being actively investigated. These include treatment with nontoxic pseudosubstrate inhibitors of MGMT, such as O(6)-benzylguanine, or RNA interference-mediated gene silencing of MGMT. However, systemic application of MGMT inhibitors is limited by an increase in hematologic toxicity. Another strategy is to deplete MGMT activity in tumor tissue using a dose-dense temozolomide schedule. These alternative schedules are well tolerated; however, it remains unclear whether they are more effective than the standard dosing regimen or whether they effectively deplete MGMT activity in tumor tissue. Of note, not all patients with glioblastoma having MGMT promoter methylation respond to alkylating agents, and even those who respond will inevitably experience relapse. Herein we review the data supporting MGMT as a major mechanism of chemotherapy resistance in malignant gliomas and describe ongoing studies that are testing resistance-modulating strategies.

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Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers.

Joshua Cohen, Ammar Javed, Christopher J Thoburn … (2017)

The earlier diagnosis of cancer is one of the keys to reducing cancer deaths in the future. Here we describe our efforts to develop a noninvasive blood test for the detection of pancreatic ductal adenocarcinoma. We combined blood tests for KRAS gene mutations with carefully thresholded protein biomarkers to determine whether the combination of these markers was superior to any single marker. The cohort tested included 221 patients with resectable pancreatic ductal adenocarcinomas and 182 control patients without known cancer. KRAS mutations were detected in the plasma of 66 patients (30%), and every mutation found in the plasma was identical to that subsequently found in the patient's primary tumor (100% concordance). The use of KRAS in conjunction with four thresholded protein biomarkers increased the sensitivity to 64%. Only one of the 182 plasma samples from the control cohort was positive for any of the DNA or protein biomarkers (99.5% specificity). This combinatorial approach may prove useful for the earlier detection of many cancer types.

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Heterogeneity maintenance in glioblastoma: a social network.

Rudy Bonavia, Maria-del-Mar Inda, Webster Cavenee … (2011)

Glioblastoma multiforme (GBM), the most common intracranial tumor in adults, is characterized by extensive heterogeneity at the cellular and molecular levels. This insidious feature arises inevitably in almost all cancers and has great significance for the general outcome of the malignancy, because it confounds our understanding of the disease and also intrinsically contributes to the tumor's aggressiveness and poses an obstacle to the design of effective therapies. The classic view that heterogeneity arises as the result of a tumor's "genetic chaos" and the more contemporary cancer stem cell (CSC) hypothesis tend to identify a single cell population as the therapeutic target: the prevailing clone over time in the first case and the CSC in the latter. However, there is growing evidence that the different tumor cell populations may not be simple bystanders. Rather, they can establish a complex network of interactions between each other and with the tumor microenvironment that eventually strengthens tumor growth and increases chances to escape therapy. These differing but complementary ideas about the origin and maintenance of tumor heterogeneity and its importance in GBM are reviewed here.

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Journal

Journal ID (nlm-ta): Cells

Journal ID (iso-abbrev): Cells

Journal ID (publisher-id): cells

Title: Cells

Publisher: MDPI

ISSN (Electronic): 2073-4409

Publication date (Electronic): 09 August 2019

Publication date Collection: August 2019

Volume: 8

Issue: 8

Electronic Location Identifier: 863

Affiliations

[1 ]N. I. Pirogov Russian National Medical University, Russian Federal Ministry of Health, 117997 Moscow, Russia

[2 ]Federal State Institution V. P. Serbsky Federal Medical Research Center of Psychiatry and Narcology National Scientific Research Center on Addictions of the Ministry of Healthcare of the Russian Federation, 119002 Moscow, Russia

[3 ]Department of Biomedical and Biotechnlogical Sciences, University of Catania, 95123 Catania, Italy

[4 ]Research Center for Prevention, Diagnosis and Treatment of Cancer, University of Catania, 95123 Catania, Italy

[5 ]Department of Fundamental and Applied Neurobiology, Serbsky National Research Center for Social and Forensic Psychiatry, Ministry of Health and Social Development of the Russian Federation, 119034 Moscow, Russia

[6 ]Laboratory of Anatomy-Histology-Embryology, Medical School of Heraklion, University of Crete, Voutes, 71110 Heraklion, Crete, Greece

[7 ]Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov, First Moscow State Medical University of the Ministry of Healthcare of the Russian Federation (Sechenov University), 119048 Moscow, Russia

[8 ]Institute of Cancer Therapeutics, University of Bradford, West Yorkshire BD7 1DP, UK

[9 ]Department of Neurology, School of Medicine, University of Crete, 71110 Heraklion, Crete, Greece

[10 ]Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA

[11 ]Centre of Toxicology Science and Research, Faculty of Medicine, University of Crete, 71003 Heraklion, Greece

[12 ]Department of Analytical Toxicology, Sechenov University, 119048 Moscow, Russia

Author notes

[* ]Correspondence: luca.falzone@ 123456unict.it (L.F.); m.libra@ 123456unict.it (M.L.); Tel.: +39-095-478-1278 (L.F.); +39-095-478-1271 (M.L.)

[†]

These authors contribute equally to this work.

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Panayiotis D. Mitsias https://orcid.org/0000-0002-9089-4954

Article

Publisher ID: cells-08-00863

DOI: 10.3390/cells8080863

PMC ID: 6721640

PubMed ID: 31405017

SO-VID: 116750e3-ef68-4b9a-b0ef-abf1be5f232e

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Current and Future Trends on Diagnosis and Prognosis of Glioblastoma: From Molecular Biology to Proteomics

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Journal of Circulating Biomarkers

Most cited references 160

Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity.

Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers.

Heterogeneity maintenance in glioblastoma: a social network.

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