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Cancers
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Resistance Mechanisms in Malignant Brain Tumors
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Resistance Mechanisms in Malignant Brain Tumors

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 35931

Special Issue Editors

Dr. Giorgio Seano

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Guest Editor
Tumor Microenvironment Laboratory, Institut Curie Research Center, Inserm U1021 CNRS UMR3347, 91405 Orsay, France
Interests: glioblastoma; brain tumors; resistance mechanisms; tumor microenvironment; vasculature; vessel co-option; biomechanics
Dr. Thomas Daubon

E-Mail Website
Guest Editor
BioDynaMit Group, Glioblastoma Metabolism, IBGC―CNRS UMR5095, University of Bordeaux, 1, rue Camille Saint Saens, 33077 Bordeaux, France
Interests: glioblastoma; metabolism; lactate; tumor invasion; tumor symbiosis; resistance mechanisms
Dr. Anna Golebiewska

E-Mail Website
Guest Editor
NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg, Luxembourg
Interests: brain tumors; glioblastoma; tumor heterogeneity; tumor plasticity; cancer stem cells; tumor microenvironment; preclinical models

Special Issue Information

Dear Colleagues,

Brain tumors comprise a broad range of primary and metastatic tumors, with different aggressiveness and clinical outcomes. Glioblastoma (GBM), and secondary metastatic tumors from distant organs, such as melanoma, lymphoma, lung and breast cancers, are among the most deadly and incurable types of human cancer. Despite improved surgical interventions, brain tumors can often be only partially removed, and only a limited amount of progress has been made to improve the patient survival in the recent years. The standard treatments are currently not effective, because malignant brain tumors are highly resistant to therapies, such as radiation, chemo- and immunotherapy. The mechanisms of resistance can be intrinsic or acquired and include:

  • Cell-autonomous mechanisms, involving undruggable genomic drivers and pathway reactivation, genomic instability, DNA damage response, intra- and inter-tumor heterogeneity, stem cell features, epigenetics and phenotypic plasticity.
  • Tumor microenvironment effects mediated by the complex crosstalk between tumor and non-malignant cells including astrocytes, neurons, vasculature (endothelial cells and pericytes), as well as distinct immune compartment of the brain comprising microglia, resident and blood-recruited macrophages and lymphocytes.
  • Microanatomical and biomechanical features of the tumor itself, such as the inefficient drug delivery, hypoxia and acidosis, tumor infiltration and invasion, vessel co-option and angiogenesis.

This Special Issue will focus on the tumor features and mechanisms that convey resistance to therapy in malignant brain tumors. We invite authors to submit contributions that provide novel findings, or reviews that comprehensively highlight the latest discoveries in the field.

text

Dr. Giorgio Seano
Dr. Thomas Daubon
Dr. Anna Golebiewska
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • brain tumors
  • resistance mechanisms
  • tumor microenvironment
  • targeted therapy
  • tumor heterogeneity
  • glioblastoma
  • brain metastasis
  • radiotherapy
  • chemotherapy
  • immunotherapy

Published Papers (11 papers)

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Research

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15 pages, 2772 KiB  
Article
An Orthotopic Model of Glioblastoma Is Resistant to Radiodynamic Therapy with 5-AminoLevulinic Acid
by Charles Dupin, Jade Sutter, Samuel Amintas, Marie-Alix Derieppe, Magalie Lalanne, Soule Coulibaly, Joris Guyon, Thomas Daubon, Julian Boutin, Jean-Marc Blouin, Emmanuel Richard, François Moreau-Gaudry, Aurélie Bedel, Véronique Vendrely and Sandrine Dabernat
Cancers 2022, 14(17), 4244; https://doi.org/10.3390/cancers14174244 - 31 Aug 2022
Cited by 4 | Viewed by 1597
Abstract
Radiosensitization of glioblastoma is a major ambition to increase the survival of this incurable cancer. The 5-aminolevulinic acid (5-ALA) is metabolized by the heme biosynthesis pathway. 5-ALA overload leads to the accumulation of the intermediate fluorescent metabolite protoporphyrin IX (PpIX) with a radiosensitization [...] Read more.
Radiosensitization of glioblastoma is a major ambition to increase the survival of this incurable cancer. The 5-aminolevulinic acid (5-ALA) is metabolized by the heme biosynthesis pathway. 5-ALA overload leads to the accumulation of the intermediate fluorescent metabolite protoporphyrin IX (PpIX) with a radiosensitization potential, never tested in a relevant model of glioblastoma. We used a patient-derived tumor cell line grafted orthotopically to create a brain tumor model. We evaluated tumor growth and tumor burden after different regimens of encephalic multifractionated radiation therapy with or without 5-ALA. A fractionation scheme of 5 × 2 Gy three times a week resulted in intermediate survival [48–62 days] compared to 0 Gy (15–24 days), 3 × 2 Gy (41–47 days) and, 5 × 3 Gy (73–83 days). Survival was correlated to tumor growth. Tumor growth and survival were similar after 5 × 2 Gy irradiations, regardless of 5-ALA treatment (RT group (53–67 days), RT+5-ALA group (40–74 days), HR = 1.57, p = 0.24). Spheroid growth and survival were diminished by radiotherapy in vitro, unchanged by 5-ALA pre-treatment, confirming the in vivo results. The analysis of two additional stem-like patient-derived cell lines confirmed the absence of radiosensitization by 5-ALA. Our study shows for the first time that in a preclinical tumor model relevant to human glioblastoma, treated as in clinical routine, 5-ALA administration, although leading to important accumulation of PpIX, does not potentiate radiotherapy. Full article
(This article belongs to the Special Issue Resistance Mechanisms in Malignant Brain Tumors)
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21 pages, 8708 KiB  
Article
Refining the Role of Pyruvate Dehydrogenase Kinases in Glioblastoma Development
by Claire M. Larrieu, Simon Storevik, Joris Guyon, Antonio C. Pagano Zottola, Cyrielle L. Bouchez, Marie-Alix Derieppe, Tuan Zea Tan, Hrvoje Miletic, James Lorens, Karl Johan Tronstad, Thomas Daubon and Gro Vatne Røsland
Cancers 2022, 14(15), 3769; https://doi.org/10.3390/cancers14153769 - 02 Aug 2022
Cited by 7 | Viewed by 2263
Abstract
Glioblastoma (GB) are the most frequent brain cancers. Aggressive growth and limited treatment options induce a median survival of 12–15 months. In addition to highly proliferative and invasive properties, GB cells show cancer-associated metabolic characteristics such as increased aerobic glycolysis. Pyruvate dehydrogenase (PDH) [...] Read more.
Glioblastoma (GB) are the most frequent brain cancers. Aggressive growth and limited treatment options induce a median survival of 12–15 months. In addition to highly proliferative and invasive properties, GB cells show cancer-associated metabolic characteristics such as increased aerobic glycolysis. Pyruvate dehydrogenase (PDH) is a key enzyme complex at the crossroads between lactic fermentation and oxidative pathways, finely regulated by PDH kinases (PDHKs). PDHKs are often overexpressed in cancer cells to facilitate high glycolytic flux. We hypothesized that targeting PDHKs, by disturbing cancer metabolic homeostasis, would alter GB progression and render cells vulnerable to additional cancer treatment. Using patient databases, distinct expression patterns of PDHK1 and PDHK2 in GB tissues were obvious. To disturb protumoral glycolysis, we modulated PDH activity through the genetic or pharmacological inhibition of PDHK in patient-derived stem-like spheroids. Striking effects of PDHKs inhibition using dichloroacetate were observed in vitro on cell morphology and metabolism, resulting in increased intracellular ROS levels and decreased proliferation and invasion. In vivo findings confirmed a reduction in tumor size and better survival of mice implanted with PDHK1 and PDHK2 knockout cells. Adding a radiotherapeutic protocol further resulted in a reduction in tumor size and improved mouse survival in our model. Full article
(This article belongs to the Special Issue Resistance Mechanisms in Malignant Brain Tumors)
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21 pages, 4741 KiB  
Article
Characterization of Temozolomide Resistance Using a Novel Acquired Resistance Model in Glioblastoma Cell Lines
by Yuan Zhu, Zhen Chen, Su Na Kim, Chao Gan, Tatsiana Ryl, Michaela Silvia Lesjak, Jan Rodemerk, Rong De Zhong, Karsten Wrede, Philipp Dammann and Ulrich Sure
Cancers 2022, 14(9), 2211; https://doi.org/10.3390/cancers14092211 - 28 Apr 2022
Cited by 8 | Viewed by 2644
Abstract
Temozolomide (TMZ) is the first line of standard therapy in glioblastoma (GBM). However, relapse occurs due to TMZ resistance. We attempted to establish an acquired TMZ resistance model that recapitulates the TMZ resistance phenotype and the relevant gene signature. Two GBM cell lines [...] Read more.
Temozolomide (TMZ) is the first line of standard therapy in glioblastoma (GBM). However, relapse occurs due to TMZ resistance. We attempted to establish an acquired TMZ resistance model that recapitulates the TMZ resistance phenotype and the relevant gene signature. Two GBM cell lines received two cycles of TMZ (150 µM) treatment for 72 h each. Regrown cells (RG2) were defined as TMZ resistant cells. MTT assay revealed significantly less susceptibility and sustained growth of RG2 compared with parental cells after TMZ challenge. TMZ-induced DNA damage significantly decreased in 53BP1-foci reporter transduced-RG2 cells compared with parental cells, associated with downregulation of MSH2 and MSH6. Flow cytometry revealed reduced G2/M arrest, increased EdU incorporation and suppressed apoptosis in RG2 cells after TMZ treatment. Colony formation and neurosphere assay demonstrated enhanced clonogenicity and neurosphere formation capacity in RG2 cells, accompanied by upregulation of stem markers. Collectively, we established an acute TMZ resistance model that recapitulated key features of TMZ resistance involving impaired mismatch repair, redistribution of cell cycle phases, increased DNA replication, reduced apoptosis and enhanced self-renewal. Therefore, this model may serve as a promising research tool for studying mechanisms of TMZ resistance and for defining therapeutic approaches to GBM in the future. Full article
(This article belongs to the Special Issue Resistance Mechanisms in Malignant Brain Tumors)
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21 pages, 2666 KiB  
Article
Dual Role of Integrin Alpha-6 in Glioblastoma: Supporting Stemness in Proneural Stem-Like Cells While Inducing Radioresistance in Mesenchymal Stem-Like Cells
by Elisabetta Stanzani, Leire Pedrosa, Guillaume Bourmeau, Oceane Anezo, Aleix Noguera-Castells, Anna Esteve-Codina, Lorena Passoni, Michela Matteoli, Núria de la Iglesia, Giorgio Seano, Fina Martínez-Soler and Avelina Tortosa
Cancers 2021, 13(12), 3055; https://doi.org/10.3390/cancers13123055 - 19 Jun 2021
Cited by 9 | Viewed by 3307
Abstract
Therapeutic resistance after multimodal therapy is the most relevant cause of glioblastoma (GBM) recurrence. Extensive cellular heterogeneity, mainly driven by the presence of GBM stem-like cells (GSCs), strongly correlates with patients’ prognosis and limited response to therapies. Defining the mechanisms that drive stemness [...] Read more.
Therapeutic resistance after multimodal therapy is the most relevant cause of glioblastoma (GBM) recurrence. Extensive cellular heterogeneity, mainly driven by the presence of GBM stem-like cells (GSCs), strongly correlates with patients’ prognosis and limited response to therapies. Defining the mechanisms that drive stemness and control responsiveness to therapy in a GSC-specific manner is therefore essential. Here we investigated the role of integrin a6 (ITGA6) in controlling stemness and resistance to radiotherapy in proneural and mesenchymal GSCs subtypes. Using cell sorting, gene silencing, RNA-Seq, and in vitro assays, we verified that ITGA6 expression seems crucial for proliferation and stemness of proneural GSCs, while it appears not to be relevant in mesenchymal GSCs under basal conditions. However, when challenged with a fractionated protocol of radiation therapy, comparable to that used in the clinical setting, mesenchymal GSCs were dependent on integrin a6 for survival. Specifically, GSCs with reduced levels of ITGA6 displayed a clear reduction of DNA damage response and perturbation of cell cycle pathways. These data indicate that ITGA6 inhibition is able to overcome the radioresistance of mesenchymal GSCs, while it reduces proliferation and stemness in proneural GSCs. Therefore, integrin a6 controls crucial characteristics across GBM subtypes in GBM heterogeneous biology and thus may represent a promising target to improve patient outcomes. Full article
(This article belongs to the Special Issue Resistance Mechanisms in Malignant Brain Tumors)
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19 pages, 2289 KiB  
Article
Targeting the RhoGEF βPIX/COOL-1 in Glioblastoma: Proof of Concept Studies
by Kate Connor, David W. Murray, Monika A. Jarzabek, Nhan L. Tran, Kieron White, Patrick Dicker, Kieron J. Sweeney, Philip J. O’Halloran, Brian MacCarthy, Liam P. Shiels, Francesca Lodi, Diether Lambrechts, Jann N. Sarkaria, Raymond M. Schiffelers, Marc Symons and Annette T. Byrne
Cancers 2020, 12(12), 3531; https://doi.org/10.3390/cancers12123531 - 26 Nov 2020
Cited by 4 | Viewed by 3262
Abstract
Glioblastoma (GBM), a highly invasive and vascular malignancy is shown to rapidly develop resistance and evolve to a more invasive phenotype following bevacizumab (Bev) therapy. Rho Guanine Nucleotide Exchange Factor proteins (RhoGEFs) are mediators of key components in Bev resistance pathways, GBM and [...] Read more.
Glioblastoma (GBM), a highly invasive and vascular malignancy is shown to rapidly develop resistance and evolve to a more invasive phenotype following bevacizumab (Bev) therapy. Rho Guanine Nucleotide Exchange Factor proteins (RhoGEFs) are mediators of key components in Bev resistance pathways, GBM and Bev-induced invasion. To identify GEFs with enhanced mRNA expression in the leading edge of GBM tumours, a cohort of GEFs was assessed using a clinical dataset. The GEF βPix/COOL-1 was identified, and the functional effect of gene depletion assessed using 3D-boyden chamber, proliferation, and colony formation assays in GBM cells. Anti-angiogenic effects were assessed in endothelial cells using tube formation and wound healing assays. In vivo effects of βPix/COOL-1-siRNA delivered via RGD-Nanoparticle in combination with Bev was studied in an invasive model of GBM. We found that siRNA-mediated knockdown of βPix/COOL-1 in vitro decreased cell invasion, proliferation and increased apoptosis in GBM cell lines. Moreover βPix/COOL-1 mediated endothelial cell migration in vitro. Mice treated with βPix/COOL-1 siRNA-loaded RGD-Nanoparticle and Bev demonstrated a trend towards improved median survival compared with Bev monotherapy. Our hypothesis generating study suggests that the RhoGEF βPix/COOL-1 may represent a target of vulnerability in GBM, in particular to improve Bev efficacy. Full article
(This article belongs to the Special Issue Resistance Mechanisms in Malignant Brain Tumors)
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15 pages, 4188 KiB  
Article
Effect of 1α,25(OH)2 Vitamin D3 in Mutant P53 Glioblastoma Cells: Involvement of Neutral Sphingomyelinase1
by Samuela Cataldi, Cataldo Arcuri, Andrea Lazzarini, Irina Nakashidze, Francesco Ragonese, Bernard Fioretti, Ivana Ferri, Carmela Conte, Michela Codini, Tommaso Beccari, Francesco Curcio and Elisabetta Albi
Cancers 2020, 12(11), 3163; https://doi.org/10.3390/cancers12113163 - 28 Oct 2020
Cited by 12 | Viewed by 3049
Abstract
Glioblastoma is one the most aggressive primary brain tumors in adults, and, despite the fact that radiation and chemotherapy after surgical approaches have been the treatments increasing the survival rates, the prognosis of patients remains poor. Today, the attention is focused on highlighting [...] Read more.
Glioblastoma is one the most aggressive primary brain tumors in adults, and, despite the fact that radiation and chemotherapy after surgical approaches have been the treatments increasing the survival rates, the prognosis of patients remains poor. Today, the attention is focused on highlighting complementary treatments that can be helpful in improving the classic therapeutic approaches. It is known that 1α,25(OH)2 vitamin D3, a molecule involved in bone metabolism, has many serendipidy effects in cells. It targets normal and cancer cells via genomic pathway by vitamin D3 receptor or via non-genomic pathways. To interrogate possible functions of 1α,25(OH)2 vitamin D3 in multiforme glioblastoma, we used three cell lines, wild-type p53 GL15 and mutant p53 U251 and LN18 cells. We demonstrated that 1α,25(OH)2 vitamin D3 acts via vitamin D receptor in GL15 cells and via neutral sphingomyelinase1, with an enrichment of ceramide pool, in U251 and LN18 cells. Changes in sphingomyelin/ceramide content were considered to be possibly responsible for the differentiating and antiproliferative effect of 1α,25(OH)2 vitamin D in U251 and LN18 cells, as shown, respectively, in vitro by immunofluorescence and in vivo by experiments of xenotransplantation in eggs. This is the first time 1α,25(OH)2 vitamin D3 is interrogated for the response of multiforme glioblastoma cells in dependence on the p53 mutation, and the results define neutral sphingomyelinase1 as a signaling effector. Full article
(This article belongs to the Special Issue Resistance Mechanisms in Malignant Brain Tumors)
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18 pages, 5472 KiB  
Article
Temozolomide-Induced RNA Interactome Uncovers Novel LncRNA Regulatory Loops in Glioblastoma
by Sabrina Fritah, Arnaud Muller, Wei Jiang, Ramkrishna Mitra, Mohamad Sarmini, Monika Dieterle, Anna Golebiewska, Tao Ye, Eric Van Dyck, Christel Herold-Mende, Zhongming Zhao, Francisco Azuaje and Simone P. Niclou
Cancers 2020, 12(9), 2583; https://doi.org/10.3390/cancers12092583 - 10 Sep 2020
Cited by 6 | Viewed by 3415
Abstract
Resistance to chemotherapy by temozolomide (TMZ) is a major cause of glioblastoma (GBM) recurrence. So far, attempts to characterize factors that contribute to TMZ sensitivity have largely focused on protein-coding genes, and failed to provide effective therapeutic targets. Long noncoding RNAs (lncRNAs) are [...] Read more.
Resistance to chemotherapy by temozolomide (TMZ) is a major cause of glioblastoma (GBM) recurrence. So far, attempts to characterize factors that contribute to TMZ sensitivity have largely focused on protein-coding genes, and failed to provide effective therapeutic targets. Long noncoding RNAs (lncRNAs) are essential regulators of epigenetic-driven cell diversification, yet, their contribution to the transcriptional response to drugs is less understood. Here, we performed RNA-seq and small RNA-seq to provide a comprehensive map of transcriptome regulation upon TMZ in patient-derived GBM stem-like cells displaying different drug sensitivity. In a search for regulatory mechanisms, we integrated thousands of molecular associations stored in public databases to generate a background “RNA interactome”. Our systems-level analysis uncovered a coordinated program of TMZ response reflected by regulatory circuits that involve transcription factors, mRNAs, miRNAs, and lncRNAs. We discovered 22 lncRNAs involved in regulatory loops and/or with functional relevance in drug response and prognostic value in gliomas. Thus, the investigation of TMZ-induced gene networks highlights novel RNA-based predictors of chemosensitivity in GBM. The computational modeling used to identify regulatory circuits underlying drug response and prioritizing gene candidates for functional validation is applicable to other datasets. Full article
(This article belongs to the Special Issue Resistance Mechanisms in Malignant Brain Tumors)
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15 pages, 3334 KiB  
Article
Sex-Specific Differences in Primary CNS Lymphoma
by Thomas Roetzer, Julia Furtner, Johanna Gesperger, Lukas Seebrecht, Dave Bandke, Martina Brada, Tanisa Brandner-Kokalj, Astrid Grams, Johannes Haybaeck, Melitta Kitzwoegerer, Stefan L. Leber, Franz Marhold, Patrizia Moser, Camillo Sherif, Johannes Trenkler, Julia Unterluggauer, Serge Weis, Franz Wuertz, Johannes A. Hainfellner, Georg Langs, Karl-Heinz Nenning and Adelheid Woehreradd Show full author list remove Hide full author list
Cancers 2020, 12(6), 1593; https://doi.org/10.3390/cancers12061593 - 16 Jun 2020
Cited by 3 | Viewed by 2612
Abstract
Sex-specific differences have been increasingly recognized in many human diseases including brain cancer, namely glioblastoma. Primary CNS lymphoma (PCNSL) is an exceedingly rare type of brain cancer that tends to have a higher incidence and worse outcomes in male patients. Yet, relatively little [...] Read more.
Sex-specific differences have been increasingly recognized in many human diseases including brain cancer, namely glioblastoma. Primary CNS lymphoma (PCNSL) is an exceedingly rare type of brain cancer that tends to have a higher incidence and worse outcomes in male patients. Yet, relatively little is known about the reasons that contribute to these observed sex-specific differences. Using a population-representative cohort of patients with PCNSL with dense magnetic resonance (MR) imaging and digital pathology annotation (n = 74), we performed sex-specific cluster and survival analyses to explore possible associations. We found three prognostically relevant clusters for females and two for males, characterized by differences in (i) patient demographics, (ii) tumor-associated immune response, and (iii) MR imaging phenotypes. Upon a multivariable analysis, an enhanced FoxP3+ lymphocyte-driven immune response was associated with a shorter overall survival particularly in female patients (HR 1.65, p = 0.035), while an increased extent of contrast enhancement emerged as an adverse predictor of outcomes in male patients (HR 1.05, p < 0.01). In conclusion, we found divergent prognostic constellations between female and male patients with PCNSL that suggest differential roles of tumor-associated immune response and MR imaging phenotypes. Our results further underline the importance of continued sex-specific analyses in the field of brain cancer. Full article
(This article belongs to the Special Issue Resistance Mechanisms in Malignant Brain Tumors)
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Review

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36 pages, 4800 KiB  
Review
Alterations in Molecular Profiles Affecting Glioblastoma Resistance to Radiochemotherapy: Where Does the Good Go?
by Juliana B. Vilar, Markus Christmann and Maja T. Tomicic
Cancers 2022, 14(10), 2416; https://doi.org/10.3390/cancers14102416 - 13 May 2022
Cited by 13 | Viewed by 3522
Abstract
Glioblastoma multiforme (GBM) is a brain tumor characterized by high heterogeneity, diffuse infiltration, aggressiveness, and formation of recurrences. Patients with this kind of tumor suffer from cognitive, emotional, and behavioral problems, beyond exhibiting dismal survival rates. Current treatment comprises surgery, radiotherapy, and chemotherapy [...] Read more.
Glioblastoma multiforme (GBM) is a brain tumor characterized by high heterogeneity, diffuse infiltration, aggressiveness, and formation of recurrences. Patients with this kind of tumor suffer from cognitive, emotional, and behavioral problems, beyond exhibiting dismal survival rates. Current treatment comprises surgery, radiotherapy, and chemotherapy with the methylating agent, temozolomide (TMZ). GBMs harbor intrinsic mutations involving major pathways that elicit the cells to evade cell death, adapt to the genotoxic stress, and regrow. Ionizing radiation and TMZ induce, for the most part, DNA damage repair, autophagy, stemness, and senescence, whereas only a small fraction of GBM cells undergoes treatment-induced apoptosis. Particularly upon TMZ exposure, most of the GBM cells undergo cellular senescence. Increased DNA repair attenuates the agent-induced cytotoxicity; autophagy functions as a pro-survival mechanism, protecting the cells from damage and facilitating the cells to have energy to grow. Stemness grants the cells capacity to repopulate the tumor, and senescence triggers an inflammatory microenvironment favorable to transformation. Here, we highlight this mutational background and its interference with the response to the standard radiochemotherapy. We discuss the most relevant and recent evidence obtained from the studies revealing the molecular mechanisms that lead these cells to be resistant and indicate some future perspectives on combating this incurable tumor. Full article
(This article belongs to the Special Issue Resistance Mechanisms in Malignant Brain Tumors)
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22 pages, 1956 KiB  
Review
Advancements, Challenges, and Future Directions in Tackling Glioblastoma Resistance to Small Kinase Inhibitors
by Federica Fabro, Martine L. M. Lamfers and Sieger Leenstra
Cancers 2022, 14(3), 600; https://doi.org/10.3390/cancers14030600 - 25 Jan 2022
Cited by 13 | Viewed by 3871
Abstract
Despite clinical intervention, glioblastoma (GBM) remains the deadliest brain tumor in adults. Its incurability is partly related to the establishment of drug resistance, both to standard and novel treatments. In fact, even though small kinase inhibitors have changed the standard clinical practice for [...] Read more.
Despite clinical intervention, glioblastoma (GBM) remains the deadliest brain tumor in adults. Its incurability is partly related to the establishment of drug resistance, both to standard and novel treatments. In fact, even though small kinase inhibitors have changed the standard clinical practice for several solid cancers, in GBM, they did not fulfill this promise. Drug resistance is thought to arise from the heterogeneity of GBM, which leads the development of several different mechanisms. A better understanding of the evolution and characteristics of drug resistance is of utmost importance to improve the current clinical practice. Therefore, the development of clinically relevant preclinical in vitro models which allow careful dissection of these processes is crucial to gain insights that can be translated to improved therapeutic approaches. In this review, we first discuss the heterogeneity of GBM, which is reflected in the development of several resistance mechanisms. In particular, we address the potential role of drug resistance mechanisms in the failure of small kinase inhibitors in clinical trials. Finally, we discuss strategies to overcome therapy resistance, particularly focusing on the importance of developing in vitro models, and the possible approaches that could be applied to the clinic to manage drug resistance. Full article
(This article belongs to the Special Issue Resistance Mechanisms in Malignant Brain Tumors)
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27 pages, 2170 KiB  
Review
Impact of Chromatin Dynamics and DNA Repair on Genomic Stability and Treatment Resistance in Pediatric High-Grade Gliomas
by Lia Pinto, Hanane Baidarjad, Natacha Entz-Werlé and Eric Van Dyck
Cancers 2021, 13(22), 5678; https://doi.org/10.3390/cancers13225678 - 12 Nov 2021
Cited by 5 | Viewed by 3867
Abstract
Despite their low incidence, pediatric high-grade gliomas (pHGGs), including diffuse intrinsic pontine gliomas (DIPGs), are the leading cause of mortality in pediatric neuro-oncology. Recurrent, mutually exclusive mutations affecting K27 (K27M) and G34 (G34R/V) in the N-terminal tail of histones H3.3 and H3.1 act [...] Read more.
Despite their low incidence, pediatric high-grade gliomas (pHGGs), including diffuse intrinsic pontine gliomas (DIPGs), are the leading cause of mortality in pediatric neuro-oncology. Recurrent, mutually exclusive mutations affecting K27 (K27M) and G34 (G34R/V) in the N-terminal tail of histones H3.3 and H3.1 act as key biological drivers of pHGGs. Notably, mutations in H3.3 are frequently associated with mutations affecting ATRX and DAXX, which encode a chaperone complex that deposits H3.3 into heterochromatic regions, including telomeres. The K27M and G34R/V mutations lead to distinct epigenetic reprogramming, telomere maintenance mechanisms, and oncogenesis scenarios, resulting in distinct subgroups of patients characterized by differences in tumor localization, clinical outcome, as well as concurrent epigenetic and genetic alterations. Contrasting with our understanding of the molecular biology of pHGGs, there has been little improvement in the treatment of pHGGs, with the current mainstays of therapy—genotoxic chemotherapy and ionizing radiation (IR)—facing the development of tumor resistance driven by complex DNA repair pathways. Chromatin and nucleosome dynamics constitute important modulators of the DNA damage response (DDR). Here, we summarize the major DNA repair pathways that contribute to resistance to current DNA damaging agent-based therapeutic strategies and describe the telomere maintenance mechanisms encountered in pHGGs. We then review the functions of H3.3 and its chaperones in chromatin dynamics and DNA repair, as well as examining the impact of their mutation/alteration on these processes. Finally, we discuss potential strategies targeting DNA repair and epigenetic mechanisms as well as telomere maintenance mechanisms, to improve the treatment of pHGGs. Full article
(This article belongs to the Special Issue Resistance Mechanisms in Malignant Brain Tumors)
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