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Background: The proportion of women among healthcare and biomedical research professionals in neuro-oncology is growing. With changes in cultural expectations and work-life balance considerations, more men aspire to nonfull-time jobs, yet, leadership positions remain dominated by men., Methods: The European Association of Neuro-Oncology (EANO) disparity committee carried out a digital survey to explore gender balance and actions suitable to promote gender equality. The survey was distributed among EANO members in 2021, with responses analyzed descriptively., Results: In total, 262 participants completed the survey (141 women, 53.8%; median age 43). Respondents were neurosurgeons (68, 26.0%); neurologists (67, 25.6%), medical oncologists (43, 16.4%), or other healthcare or research professionals; 208 participants (79.4%) worked full-time. Positive action to enforce the role of women in neuro-oncology was deemed necessary by 180 participants (68.7%), but only 28 participants (10.7%) agreed that women only should be promoted until gender balance is reached. A majority of respondents (162, 61.8%) felt that women with an equivalent CV should be prioritized over men to reach gender balance. If in the future the balance favored women at higher positions, 112 respondents (42.7%) agreed to apply positive action for men. The top indicators considered relevant to measure gender balance were: salary for similar positions (183/228, 80.3%), paid overtime (176/228, 77.2%), number of permanent positions (164/228, 71.9%), protected time for research (161/227, 70.9%), and training opportunities (157/227, 69.2%)., Conclusions: Specific indicators may help to measure and promote gender balance and should be considered for implementation among healthcare professionals in neuro-oncology., Competing Interests: E.L.R. reports personal financial interests as an advisory board member for Bayer, Janssen, Leo Pharma, Pierre Fabre, and Seattle Genetics; institutional funding from BMS. F.B. has no conflict of interest to declare. G.M. reports personal financial interests as an invited speaker for BrainLab and treasurer for the European Organisation for Research and Treatment of Cancer; institutional funding from AstraZeneca. N.G. has received honoraria for lectures from Blue Earth Diagnostics and for advisory board participation from Telix Pharmaceuticals. M.T. has no conflict of interest to declare. K.P. has no conflict of interest to declare. R.R. reports personal financial interests for advisory board membership for GENENTA, expert testimony for Novocure, and as an invited speaker for Bayer and UCB. Personal financial interests as an independent data monitoring committee member for Novocure, Servier, and CureVac. S.N. has no conflict of interest to declare. M.G. has no conflict of interest to declare. M.P. reports personal financial interests for advisory board membership for Abbvie, Adastra, AstraZeneca, Bayer, BMJ Journals, Bristol-Myers Squibb (BMS), CMC Contrast, Daiichi Sankyo, Gan & Lee Pharmaceuticals, Gerson Lehrman, GlaxoSmithKline (GSK), Lilly, Medahead, MedMedia, Merck Sharp & Dohme (MSD), Mundipharma, Novartis, Roche, Sanofi and Tocagen; institutional funding as coordinating principal investigator for PharmaMar and institutional research grants from Abbvie, Boehringer-Ingelheim, BMS, Daiichi Sankyo, GSK, MSD, Novocure and Roche. He reports non-financial interests as Past President of the European Association of Neuro-Oncology, Brain Tumor Group Chair for the European Organisation for Research and Treatment of Cancer, and as a member of the Multi-Site Guideline Advisory Group for the American Society of Clinical Oncology. M.W. reports personal financial interests as an advisory board member from Bayer, Curevac, Merck (EMD), Novartis, Novocure, and Philogen; personal financial interests as an independent data monitoring committee member for Orbus; institutional research grants from Quercis and Versameb. He also reports non-financial interests from a leadership role for the European Organisation for Research and Treatment of Cancer. S.C.S. received honoraria for lectures, advisory boards, or consultation from Bayer, Blue Earth, Tocagen, CeCaVa, and research grant funding from Apollomics. L.D. has no conflict of interest to declare., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

The mainstay of treatment for adult patients with gliomas, glioneuronal and neuronal tumors consists of combinations of surgery, radiotherapy, and chemotherapy. For many systemic cancers, targeted treatments are a part of the standard of care, however, the predictive significance of most of these targets in central nervous system (CNS) tumors remains less well-studied. Despite that, there is increasing use of advanced molecular diagnostics that identify potential targets, and tumor-agnostic regulatory approvals on targets also present in CNS tumors have been granted. This raises the question of when and for which targets it is meaningful to test in adult patients with CNS tumors. This evidence-based guideline reviews the evidence available for targeted treatment for alterations in the RAS/MAPK pathway (BRAF, NF1), in growth factor receptors (EGFR, ALK, fibroblast growth factor receptor (FGFR), neurotrophic tyrosine receptor kinase (NTRK), platelet-derived growth factor receptor alpha, and ROS1), in cell cycle signaling (CDK4/6, MDM2/4, and TSC1/2) and altered genomic stability (mismatch repair, POLE, high tumor mutational burden (TMB), homologous recombination deficiency) in adult patients with gliomas, glioneuronal and neuronal tumors. At present, targeted treatment for BRAF p.V600E alterations is to be considered part of the standard of care for patients with recurrent gliomas, pending regulatory approval. For approved tumor agnostic treatments for NTRK fusions and high TMB, the evidence for efficacy in adult patients with CNS tumors is very limited, and treatment should preferably be given within prospective clinical registries and trials. For targeted treatment of CNS tumors with FGFR fusions or mutations, clinical trials are ongoing to confirm modest activity so far observed in basket trials. For all other reviewed targets, evidence of benefit in CNS tumors is currently lacking, and testing/treatment should be in the context of available clinical trials., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Phenotypic plasticity has emerged as a major contributor to intra-tumoral heterogeneity and treatment resistance in cancer. Increasing evidence shows that glioblastoma (GBM) cells display prominent intrinsic plasticity and reversibly adapt to dynamic microenvironmental conditions. Limited genetic evolution at recurrence further suggests that resistance mechanisms also largely operate at the phenotypic level. Here we review recent literature underpinning the role of GBM plasticity in creating gradients of heterogeneous cells including those that carry cancer stem cell (CSC) properties. A historical perspective from the hierarchical to the nonhierarchical concept of CSCs towards the recent appreciation of GBM plasticity is provided. Cellular states interact dynamically with each other and with the surrounding brain to shape a flexible tumor ecosystem, which enables swift adaptation to external pressure including treatment. We present the key components regulating intra-tumoral phenotypic heterogeneity and the equilibrium of phenotypic states, including genetic, epigenetic, and microenvironmental factors. We further discuss plasticity in the context of intrinsic tumor resistance, where a variable balance between preexisting resistant cells and adaptive persisters leads to reversible adaptation upon treatment. Innovative efforts targeting regulators of plasticity and mechanisms of state transitions towards treatment-resistant states are needed to restrict the adaptive capacities of GBM., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Replication-associated single-ended DNA double-strand breaks (seDSBs) are repaired predominantly through RAD51-mediated homologous recombination (HR). Removal of the non-homologous end-joining (NHEJ) factor Ku from resected seDSB ends is crucial for HR. The coordinated actions of MRE11-CtIP nuclease activities orchestrated by ATM define one pathway for Ku eviction. Here, we identify the pre-mRNA splicing protein XAB2 as a factor required for resistance to seDSBs induced by the chemotherapeutic alkylator temozolomide. Moreover, we show that XAB2 prevents Ku retention and abortive HR at seDSBs induced by temozolomide and camptothecin, via a pathway that operates in parallel to the ATM-CtIP-MRE11 axis. Although XAB2 depletion preserved RAD51 focus formation, the resulting RAD51-ssDNA associations were unproductive, leading to increased NHEJ engagement in S/G2 and genetic instability. Overexpression of RAD51 or RAD52 rescued the XAB2 defects and XAB2 loss was synthetically lethal with RAD52 inhibition, providing potential perspectives in cancer therapy., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Mutations in isocitrate dehydrogenase 1 or 2 ( IDH1/2 ) define glioma subtypes and are considered primary events in gliomagenesis, impacting tumor epigenetics and metabolism. IDH enzyme activity is crucial for the generation of reducing potential in normal cells, yet the impact of the mutation on the cellular antioxidant system in glioma is not understood. The aim of this study was to determine how glutathione (GSH), the main antioxidant in the brain, is maintained in IDH1-mutant gliomas, despite an altered NADPH/NADP balance., Methods: Proteomics, metabolomics, metabolic tracer studies, genetic silencing, and drug targeting approaches in vitro and in vivo were applied. Analyses were done in clinical specimen of different glioma subtypes, in glioma patient-derived cell lines carrying the endogenous IDH1 mutation and corresponding orthotopic xenografts in mice., Results: We find that cystathionine-γ-lyase (CSE), the enzyme responsible for cysteine production upstream of GSH biosynthesis, is specifically upregulated in IDH1-mutant astrocytomas. CSE inhibition sensitized these cells to cysteine depletion, an effect not observed in IDH1 wild-type gliomas. This correlated with an increase in reactive oxygen species and reduced GSH synthesis. Propargylglycine (PAG), a brain-penetrant drug specifically targeting CSE, led to delayed tumor growth in mice., Conclusions: W e show that IDH1-mutant astrocytic gliomas critically rely on NADPH-independent de novo GSH synthesis via CSE to maintain the antioxidant defense, which highlights a novel metabolic vulnerability that may be therapeutically exploited., (© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: Women represent an increasing proportion of the overall workforce in medicine but are underrepresented in leadership roles., Methods: To explore gender inequalities and challenges in career opportunities, a web-based survey was conducted among the membership of the European Association of Neuro-Oncology and the Brain Tumor Group of the European Organisation for Research and Treatment of Cancer., Results: A total of 228 colleagues responded to the survey: 129 women (median age 45 years; range, 25-66 years) and 99 men (median age 48 years; range, 24-81 years); 153 participants (67%) were married and 157 participants (69%) had at least 1 child. Women less often declared being married (60% vs 77%, P = .007) or having a child (63% vs 77%, P = .024). Men more frequently had a full-time position (88% vs 75%, P = .036). Women and men both perceived an underrepresentation of women in leadership positions. Half of participants agreed that the most important challenges for women are leading a team and obtaining a faculty position. Fewer women than men would accept such a position (42% vs 56%). The main reasons were limited time for career and an inappropriate work and life balance. Women specifically cited negative discrimination, limited opportunities, and lack of self-confidence. Discrimination of women at work was perceived by 64% of women vs 47% of men ( P = .003)., Conclusion: Women are perceived as experiencing more difficulties in acquiring a leadership position. Personal preferences may account for an underrepresentation of women in leadership positions, but perceived gender inequalities extend beyond disparities of access to leadership., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Targeted approaches for inhibiting epidermal growth factor receptor (EGFR) and other receptor tyrosine kinases (RTKs) in glioblastoma (GBM) have led to therapeutic resistance and little clinical benefit, raising the need for the development of alternative strategies. Endogenous LRIG1 (Leucine-rich Repeats and ImmunoGlobulin-like domains protein 1) is an RTK inhibitory protein required for stem cell maintenance, and we previously demonstrated the soluble ectodomain of LRIG1 (sLRIG1) to potently inhibit GBM growth in vitro and in vivo., Methods: Here, we generated a recombinant protein of the ectodomain of LRIG1 (sLRIG1) and determined its activity in various cellular GBM models including patient-derived stem-like cells and patient organoids. We used proliferation, adhesion, and invasion assays, and performed gene and protein expression studies. Proximity ligation assay and NanoBiT complementation technology were applied to assess protein-protein interactions., Results: We show that recombinant sLRIG1 downregulates EGFRvIII but not EGFR, and reduces proliferation in GBM cells, irrespective of their EGFR expression status. We find that sLRIG1 targets and downregulates a wide range of RTKs, including AXL, and alters GBM cell adhesion. Mechanistically, we demonstrate that LRIG1 interferes with AXL but not with EGFR dimerization., Conclusions: These results identify AXL as a novel sLRIG1 target and show that LRIG1-mediated RTK downregulation depends on direct protein interaction. The pan -RTK inhibitory activity of sLRIG1 warrants further investigation for new GBM treatment approaches., (© The Author(s) 2019. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: Invasion and angiogenesis are major hallmarks of glioblastoma (GBM) growth. While invasive tumor cells grow adjacent to blood vessels in normal brain tissue, tumor cells within neovascularized regions exhibit hypoxic stress and promote angiogenesis. The distinct microenvironments likely differentially affect metabolic processes within the tumor cells., Methods: In the present study, we analyzed gene expression and metabolic changes in a human GBM xenograft model that displayed invasive and angiogenic phenotypes. In addition, we used glioma patient biopsies to confirm the results from the xenograft model., Results: We demonstrate that the angiogenic switch in our xenograft model is linked to a proneural-to-mesenchymal transition that is associated with upregulation of the transcription factors BHLHE40, CEBPB, and STAT3. Metabolic analyses revealed that angiogenic xenografts employed higher rates of glycolysis compared with invasive xenografts. Likewise, patient biopsies exhibited higher expression of the glycolytic enzyme lactate dehydrogenase A and glucose transporter 1 in hypoxic areas compared with the invasive edge and lower-grade tumors. Analysis of the mitochondrial respiratory chain showed reduction of complex I in angiogenic xenografts and hypoxic regions of GBM samples compared with invasive xenografts, nonhypoxic GBM regions, and lower-grade tumors. In vitro hypoxia experiments additionally revealed metabolic adaptation of invasive tumor cells, which increased lactate production under long-term hypoxia., Conclusions: The use of glycolysis versus mitochondrial respiration for energy production within human GBM tumors is highly dependent on the specific microenvironment. The metabolic adaptability of GBM cells highlights the difficulty of targeting one specific metabolic pathway for effective therapeutic intervention., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Background: Amplification of the epidermal growth factor receptor (EGFR) and its mutant EGFRvIII are among the most common genetic alterations in glioblastoma (GBM), the most frequent and most aggressive primary brain tumor., Methods: In the present work, we analyzed the clonal evolution of these major EGFR aberrations in a small cohort of GBM patients using a unique surgical multisampling technique. Furthermore, we overexpressed both receptors separately and together in 2 patient-derived GBM stem cell lines (GSCs) to analyze their functions in vivo in orthotopic xenograft models., Results: In human GBM biopsies, we identified EGFR amplification as an early event because EGFRvIII mutations emerge from intratumoral heterogeneity later in tumor development. To investigate the biological relevance of this distinct developmental pattern, we established experimental model systems. In these models, EGFR + tumor cells showed activation of classical downstream signaling pathways upon EGF stimulation and displayed enhanced invasive growth without evidence of angiogenesis in vivo. In contrast, EGFRvIII + tumors were driven by activation of the prototypical Src family kinase c-Src that promoted VEGF secretion leading to angiogenic tumor growth., Conclusions: The presented work shows that sequential EGFR amplification and EGFRvIII mutations might represent concerted evolutionary events that drive the aggressive nature of GBM by promoting invasion and angiogenesis via distinct signaling pathways. In particular, c-SRC may be an attractive therapeutic target for tumors harboring EGFRvIII as we identified this protein specifically mediating angiogenic tumor growth downstream of EGFRvIII., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Deregulated growth factor signaling is a major driving force in the initiation and progression of glioblastoma. The tumor suppressor and stem cell marker Lrig1 is a negative regulator of the epidermal growth factor receptor (EGFR) family. Here, we addressed the therapeutic potential of the soluble form of Lrig1 (sLrig1) in glioblastoma treatment and the mechanism of sLrig1-induced growth inhibition., Methods: With use of encapsulated cells, recombinant sLrig1 was locally delivered in orthotopic glioblastoma xenografts generated from freshly isolated patient tumors. Tumor growth and mouse survival were evaluated. The efficacy of sLrig1 and the affected downstream signaling was studied in vitro and in vivo in glioma cells displaying variable expression of wild-type and/or a constitutively active EGFR mutant (EGFRvIII)., Results: Continuous interstitial delivery of sLrig1 in genetically diverse patient-derived glioma xenografts led to strong tumor growth inhibition. Glioma cell proliferation in vitro and tumor growth in vivo were potently inhibited by sLrig1, irrespective of EGFR expression levels. Of importance, tumor growth was also suppressed in EGFRvIII-driven glioma. sLrig1 induced cell cycle arrest without changing total receptor level or phosphorylation. Affected downstream effectors included MAP kinase but not AKT signaling. Of importance, local delivery of sLrig1 into established tumors led to a 32% survival advantage in treated mice., Conclusions: To our knowledge, this is the first report demonstrating that sLrig1 is a potent inhibitor of glioblastoma growth in clinically relevant experimental glioma models and that this effect is largely independent of EGFR status. The potent anti-tumor effect of sLrig1, in combination with cell encapsulation technology for in situ delivery, holds promise for future treatment of glioblastoma.

The identification and significance of cancer stem-like cells in malignant gliomas remains controversial. It has been proposed that cancer stem-like cells display increased drug resistance, through the expression of ATP-binding cassette transporters that detoxify cells by effluxing exogenous compounds. Here, we investigated the 'side population' phenotype based on efflux properties of ATP-binding cassette transporters in freshly isolated human glioblastoma samples and intracranial xenografts derived thereof. Using fluorescence in situ hybridization analysis on sorted cells obtained from glioblastoma biopsies, as well as human tumour xenografts developed in immunodeficient enhanced green fluorescence protein-expressing mice that allow an unequivocal tumour-stroma discrimination, we show that side population cells in human glioblastoma are non-neoplastic and exclusively stroma-derived. Tumour cells were consistently devoid of efflux properties regardless of their genetic background, tumour ploidy or stem cell associated marker expression. Using multi-parameter flow cytometry we identified the stromal side population in human glioblastoma to be brain-derived endothelial cells with a minor contribution of astrocytes. In contrast with their foetal counterpart, neural stem/progenitor cells in the adult brain did not display the side population phenotype. Of note, we show that CD133-positive cells often associated with cancer stem-like cells in glioblastoma biopsies, do not represent a homogenous cell population and include CD31-positive endothelial cells. Interestingly, treatment of brain tumours with the anti-angiogenic agent bevacizumab reduced total vessel density, but did not affect the efflux properties of endothelial cells. In conclusion our findings contribute to an unbiased identification of cancer stem-like cells and stromal cells in brain neoplasms, and provide novel insight into the complex issue of drug delivery to the brain. Since efflux properties of endothelial cells are likely to compromise drug availability, transiently targeting ATP-binding cassette transporters may be a valuable therapeutic strategy to improve treatment effects in brain tumours.

Animal modeling for primary brain tumors has undergone constant development over the last 60 years, and significant improvements have been made recently with the establishment of highly invasive glioblastoma models. In this review we discuss the advantages and pitfalls of model development, focusing on chemically induced models, various xenogeneic grafts of human cell lines, including stem cell-like cell lines and biopsy spheroids. We then discuss the development of numerous genetically engineered models available to study mechanisms of tumor initiation and progression. At present it is clear that none of the current animal models fully reflects human gliomas. Yet, the various model systems have provided important insight into specific mechanisms of tumor development. In particular, it is anticipated that a combined comprehensive knowledge of the various models currently available will provide important new knowledge on target identification and the validation and development of new therapeutic strategies.