bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2024–11–24
23 papers selected by
Oltea Sampetrean, Keio University
  1. Single-cell multi-omics sequencing uncovers region-specific plasticity of glioblastoma for complementary therapeutic targeting.
  2. Neuroimmune-competent human brain organoid model of Diffuse Midline Glioma.
  3. Diffuse pediatric high-grade glioma of methylation-based RTK2A and RTK2B subclasses present distinct radiological and histomolecular features including Gliomatosis cerebri phenotype.
  4. Treatment of glioblastoma patients with personalized vaccines outside clinical trials: Lessons ignored?
  5. The power of three: hypofractionation, protons, and molecular imaging in glioblastoma radiotherapy.
  6. Gliocidin is a nicotinamide-mimetic prodrug that targets glioblastoma.
  7. Longitudinal multimodal profiling of IDH-wildtype glioblastoma reveals the molecular evolution and cellular phenotypes underlying prognostically different treatment responses.
  8. Phase 2 Trial of Veliparib, Local Irradiation and Temozolomide in Patients with Newly Diagnosed High-Grade Glioma: A Children's Oncology Group Study.
  9. Brain-penetrating molecule might offer a route to treat glioblastoma tumours.
  10. Glutaminolysis is associated with mitochondrial pathway activation and can be therapeutically targeted in glioblastoma.
  11. Generation and banking of patient-derived glioblastoma organoid and its application in cancer neuroscience.
  12. An E2 ubiquitin-conjugating enzyme links diubiquitinated H2B to H3K27M oncohistone function.
  13. Inhibition of Mitochondrial Bioenergetics and Hypoxia to Radiosensitize Diffuse Intrinsic Pontine Glioma.
  14. Proteomic profiling of gliomas unveils immune and metabolism-driven subtypes with implications for anti-nucleotide metabolism therapy.
  15. Clinical and Genetic Markers of Vascular Toxicity in Glioblastoma Patients: Insights from NRG Oncology RTOG-0825.
  16. Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.
  17. Biological and prognostic relevance of epigenetic regulatory genes in high-grade gliomas.
  18. An AMP-activated protein kinase-PGC-1α axis mediates metabolic plasticity in glioblastoma.
  19. G-quadruplex stabilizer CX-5461 effectively combines with radiotherapy to target ATRX-deficient malignant glioma.
  20. PTBP1 Lactylation Promotes Glioma Stem Cell Maintenance through PFKFB4-Driven Glycolysis.
  21. Alternative lengthening of telomere-based immortalization renders H3G34R -mutant diffuse hemispheric glioma hypersensitive to PARP inhibitor combination regimens.
  22. Integrated molecular and functional characterization of the intrinsic apoptotic machinery identifies therapeutic vulnerabilities in glioma.
  23. Evolving cell states and oncogenic drivers during the progression of IDH-mutant gliomas.
  1. Sci Adv. 2024 Nov 22. 10(47): eadn4306
    Single-cell multi-omics sequencing uncovers region-specific plasticity of glioblastoma for complementary therapeutic targeting.
    Xin Wang, Qian Sun, Tianbin Liu, Haoran Lu, Xuyi Lin, Weiwen Wang, Yang Liu, Yunting Huang, Guodong Huang, Haixi Sun, Qianxue Chen, Junmin Wang, Daofeng Tian, Fan'en Yuan, Longqi Liu, Bo Wang, Ying Gu, Baohui Liu, Liang Chen.
      Glioblastoma (GBM) cells are highly heterogeneous and invasive, leading to treatment resistance and relapse. However, the molecular regulation in and distal to tumors remains elusive. Here, we collected paired tissues from the tumor core (TC) and peritumoral brain (PTB) for integrated snRNA-seq and snATAC-seq analyses. Tumor cells infiltrating PTB from TC behave more like oligodendrocyte progenitor cells than astrocytes at the transcriptome level. Dual-omics analyses further suggest that the distal regulatory regions in the tumor genome and specific transcription factors are potential determinants of regional heterogeneity. Notably, while activator protein 1 (AP-1) is active in all GBM states, its activity declines from TC to PTB, with another transcription factor, BACH1, showing the opposite trend. Combined inhibition of AP-1 and BACH1 more efficiently attenuates the tumor progression in mice and prolongs survival than either single-target treatment. Together, our work reveals marked molecular alterations of infiltrated GBM cells and a synergy of combination therapy targeting intratumor heterogeneity in and distal to GBM.
    DOI:  https://doi.org/10.1126/sciadv.adn4306
  2. Neuro Oncol. 2024 Nov 19. pii: noae245. [Epub ahead of print]
    Neuroimmune-competent human brain organoid model of Diffuse Midline Glioma.
    Katharina Sarnow, Emma Majercak, Qurbonali Qurbonov, Gustavo A V Cruzeiro, Daeun Jeong, Ishraq A Harque, Andrew Khalil, Lissa C Baird, Mariella G Filbin, Xin Tang.
       BACKGROUND: Pediatric high-grade gliomas, such as diffuse midline glioma (DMG), have a poor prognosis and lack curative treatments. Current research models of DMG primarily rely on human DMG cell lines cultured in vitro or xenografted into the brains of immunodeficient mice. However, these models are insufficient to recapitulate the complex cell-cell interactions between DMG and the tumor immune microenvironment (TIME), therefore fall short of accurately reflecting how efficacious therapeutic agents or combinations will be in the clinical setting.
    METHODS: To address these challenges, we developed a neuroimmune-competent brain/tumor fusion organoid model system consisting entirely of human cells to investigate the interactions between DMG cells and the primary innate immune cells of the brain, microglia, in the TIME at both cellular and subcellular levels. We generated microglia-containing brain organoids (MiCBO) that carry morphologically mature, motile microglia and multiple subtypes of neurons to mimic the brain tumor microenvironment. These organoids were then fused with H3K27M mutant, TP53P27R/K132R DMG tumor spheroids to create the MiCBO-tumor fusion (MiCBO-TF) model.
    RESULTS: We utilized live imaging methods to simultaneously track the mobility of microglial cell bodies and the motility of their process, as well as the behavior of tumor cells within a human brain tissue environment. Our MiCBO-TF model faithfully recapitulated the diffuse infiltration pattern of DMG into brain tissue and revealed that microglial mobility and interactions with tumor cells are highly influenced by external factors and surrounding tissue environment.
    CONCLUSIONS: The MiCBO-TF model represents a powerful platform for both mechanistic investigations and the development of precision medicine approaches for DMG.
    Keywords:  DMG; brain organoid; infiltration; microglia; tumor-immune interactions
    DOI:  https://doi.org/10.1093/neuonc/noae245
  3. Acta Neuropathol Commun. 2024 Nov 18. 12(1): 176
    Diffuse pediatric high-grade glioma of methylation-based RTK2A and RTK2B subclasses present distinct radiological and histomolecular features including Gliomatosis cerebri phenotype.
    Arnault Tauziède-Espariat, Lea L Friker, Gunther Nussbaumer, Brigitte Bison, Volodia Dangouloff-Ros, Alice Métais, David Sumerauer, Josef Zamecnik, Martin Benesch, Thomas Perwein, Dannis van Vuurden, Pieter Wesseling, Andrés Morales La Madrid, Maria Luisa Garrè, Manila Antonelli, Felice Giangaspero, Torsten Pietsch, Dominik Sturm, David T W Jones, Stefan M Pfister, Yura Grabovska, Alan Mackay, Chris Jones, Jacques Grill, Yassine Ajlil, André O von Bueren, Michael Karremann, Marion Hoffmann, Christof M Kramm, Robert Kwiecien, David Castel, Gerrit H Gielen, Pascale Varlet.
      Diffuse pediatric-type high-grade gliomas (pedHGG), H3- and IDH-wildtype, encompass three main DNA-methylation-based subtypes: pedHGG-MYCN, pedHGG-RTK1A/B/C, and pedHGG-RTK2A/B. Since their first description in 2017 tumors of pedHGG-RTK2A/B have not been comprehensively characterized and clinical correlates remain elusive. In a recent series of pedHGG with a Gliomatosis cerebri (GC) growth pattern, an increased incidence of pedHGG-RTK2A/B (n = 18) was observed. We added 14 epigenetically defined pedHGG-RTK2A/B tumors to this GC series and provided centrally reviewed radiological, histological, and molecular characterization. The final cohort of 32 pedHGG-RTK2A/B tumors consisted of 25 pedHGG-RTK2A (78%) and seven pedHGG-RTK2B (22%) cases. The median age was 11.6 years (range, 4-17) with a median overall survival of 16.0 months (range 10.9-28.2). Seven of 11 of the newly added cases with imaging available showed a GC phenotype at diagnosis or follow-up. PedHGG-RTK2B tumors exhibited frequent bithalamic involvement (6/7, 86%). Central neuropathology review confirmed a diffuse glial neoplasm in all tumors with prominent angiocentric features in both subclasses. Most tumors (24/27 with available data, 89%) diffusely expressed EGFR with focal angiocentric enhancement. PedHGG-RTK2A tumors lacked OLIG2 expression, whereas 43% (3/7) of pedHGG-RTK2B expressed this glial transcription factor. ATRX loss occurred in 3/6 pedHGG-RTK2B samples with available data (50%). DNA sequencing (pedHGG-RTK2A: n = 18, pedHGG-RTK2B: n = 5) found EGFR alterations (15/23, 65%; predominantly point mutations) in both subclasses. Mutations in BCOR (14/18, 78%), SETD2 (7/18, 39%), and the hTERT promoter (7/19, 37%) occurred exclusively in pedHGG-RTK2A tumors, while pedHGG-RTK2B tumors were enriched for TP53 alterations (4/5, 80%). In conclusion, pedHGG-RTK2A/B tumors are characterized by highly diffuse-infiltrating growth patterns and specific radiological and histo-molecular features. By comprehensively characterizing methylation-based tumors, the chance to develop specific and effective therapy concepts for these detrimental tumors increases.
    Keywords:  Gliomatosis cerebri; Methylation; Pediatric high-grade glioma; RTK2A; RTK2B; Receptor tyrosine kinase; pedHGG
    DOI:  https://doi.org/10.1186/s40478-024-01881-1
  4. Neuro Oncol. 2024 Nov 19. pii: noae225. [Epub ahead of print]
    Treatment of glioblastoma patients with personalized vaccines outside clinical trials: Lessons ignored?
    Ghazaleh Tabatabai, Michael Platten, Matthias Preusser, Michael Weller, Wolfgang Wick, Martin van den Bent.
      
    Keywords:  glioblastoma; historical controls; immunotherapy; personalized vaccines; real world
    DOI:  https://doi.org/10.1093/neuonc/noae225
  5. Lancet Oncol. 2024 Nov 18. pii: S1470-2045(24)00633-8. [Epub ahead of print]
    The power of three: hypofractionation, protons, and molecular imaging in glioblastoma radiotherapy.
    Eric A Mellon.
      
    DOI:  https://doi.org/10.1016/S1470-2045(24)00633-8
  6. Nature. 2024 Nov 20.
    Gliocidin is a nicotinamide-mimetic prodrug that targets glioblastoma.
    Yu-Jung Chen, Swathi V Iyer, David Chun-Cheng Hsieh, Buren Li, Harold K Elias, Tao Wang, Jing Li, Mungunsarnai Ganbold, Michelle C Lien, Yu-Chun Peng, Xuanhua P Xie, Chenura D Jayewickreme, Marcel R M van den Brink, Sean F Brady, S Kyun Lim, Luis F Parada.
      Glioblastoma is incurable and in urgent need of improved therapeutics1. Here we identify a small compound, gliocidin, that kills glioblastoma cells while sparing non-tumour replicative cells. Gliocidin activity targets a de novo purine synthesis vulnerability in glioblastoma through indirect inhibition of inosine monophosphate dehydrogenase 2 (IMPDH2). IMPDH2 blockade reduces intracellular guanine nucleotide levels, causing nucleotide imbalance, replication stress and tumour cell death2. Gliocidin is a prodrug that is anabolized into its tumoricidal metabolite, gliocidin-adenine dinucleotide (GAD), by the enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) of the NAD+ salvage pathway. The cryo-electron microscopy structure of GAD together with IMPDH2 demonstrates its entry, deformation and blockade of the NAD+ pocket3. In vivo, gliocidin penetrates the blood-brain barrier and extends the survival of mice with orthotopic glioblastoma. The DNA alkylating agent temozolomide induces Nmnat1 expression, causing synergistic tumour cell killing and additional survival benefit in orthotopic patient-derived xenograft models. This study brings gliocidin to light as a prodrug with the potential to improve the survival of patients with glioblastoma.
    DOI:  https://doi.org/10.1038/s41586-024-08224-z
  7. Neuro Oncol. 2024 Nov 19. pii: noae214. [Epub ahead of print]
    Longitudinal multimodal profiling of IDH-wildtype glioblastoma reveals the molecular evolution and cellular phenotypes underlying prognostically different treatment responses.
    Calixto-Hope G Lucas, Nadeem N Al-Adli, Jacob S Young, Rohit Gupta, Ramin A Morshed, Jasper Wu, Ajay Ravindranathan, Anny Shai, Nancy Ann Oberheim Bush, Jennie W Taylor, John de Groot, Javier E Villanueva-Meyer, Melike Pekmezci, Arie Perry, Andrew W Bollen, Philip V Theodosopoulos, Manish K Aghi, Edward F Chang, Shawn L Hervey-Jumper, David R Raleigh, Annette M Molinaro, Joseph F Costello, Aaron A Diaz, Jennifer L Clarke, Nicholas A Butowski, Joanna J Phillips, Susan M Chang, Mitchel S Berger, David A Solomon.
       BACKGROUND: Despite recent advances in the biology of IDH-wildtype glioblastoma, it remains a devastating disease with median survival of less than 2 years. However, the molecular underpinnings of the heterogeneous response to the current standard-of-care treatment regimen consisting of maximal safe resection, adjuvant radiation, and chemotherapy with temozolomide remain unknown.
    METHODS: Comprehensive histopathologic, genomic, and epigenomic evaluation of paired initial and recurrent glioblastoma specimens from 106 patients was performed to investigate the molecular evolution and cellular phenotypes underlying differential treatment responses.
    RESULTS: While TERT promoter mutation and CDKN2A homozygous deletion were early events during gliomagenesis shared by initial and recurrent tumors, most other recurrent genetic alterations (eg, EGFR, PTEN, and NF1) were commonly private to initial or recurrent tumors indicating acquisition later during clonal evolution. Furthermore, glioblastomas exhibited heterogeneous epigenomic evolution with subsets becoming more globally hypermethylated, hypomethylated, or remaining stable. Glioblastoma that underwent sarcomatous transformation had shorter interval to recurrence and were significantly enriched in NF1, TP53, and RB1 alterations and the mesenchymal epigenetic class. Patients who developed somatic hypermutation following temozolomide treatment had significantly longer interval to disease recurrence and prolonged overall survival, and increased methylation at 4 specific CpG sites in the promoter region of MGMT was significantly associated with this development of hypermutation. Finally, an epigenomic evolution signature incorporating change in DNA methylation levels across 347 critical CpG sites was developed that significantly correlated with clinical outcomes.
    CONCLUSIONS: Glioblastoma undergoes heterogeneous genetic, epigenetic, and cellular evolution that underlies prognostically different treatment responses.
    Keywords:  DNA methylation; glioblastoma; gliosarcoma; molecular neuropathology; temozolomide-induced hypermutation
    DOI:  https://doi.org/10.1093/neuonc/noae214
  8. Neuro Oncol. 2024 Nov 19. pii: noae247. [Epub ahead of print]
    Phase 2 Trial of Veliparib, Local Irradiation and Temozolomide in Patients with Newly Diagnosed High-Grade Glioma: A Children's Oncology Group Study.
    Matthias A Karajannis, Arzu Onar-Thomas, Tong Lin, Patricia A Baxter, Daniel R Boué, Bonnie L Cole, Christine Fuller, Sofia Haque, Nada Jabado, John T Lucas, Shannon M MacDonald, Celeste Matsushima, Namrata Patel, Christopher R Pierson, Mark M Souweidane, Diana L Thomas, Michael F Walsh, Wafik Zaky, Sarah E S Leary, Amar Gajjar, Maryam Fouladi, Kenneth J Cohen.
       BACKGROUND: The outcome for pediatric patients with high-grade glioma (HGG) remains poor. Veliparib, a potent oral poly(adenosine diphosphate-ribose) polymerase (PARP) 1/2 inhibitor, enhances the activity of radiotherapy and DNA-damaging chemotherapy.
    METHODS: We conducted a single-arm, non-randomized phase 2 clinical trial to determine whether treatment with veliparib and radiotherapy, followed by veliparib and temozolomide, improves progression-free survival in pediatric patients with newly diagnosed HGG without H3 K27M or BRAF mutations compared to patient level data from historical cohorts with closely matching clinical and molecular features. Following surgical resection, newly diagnosed children with non-metastatic HGG were screened by rapid central pathology review and molecular testing. Eligible patients were enrolled on Stratum 1 (IDH wild-type) or Stratum 2 (IDH mutant).
    RESULTS: Both strata were closed to accrual for futility after planned interim analyses. Among the 23 eligible patients who enrolled on Stratum 1 and received protocol therapy, the 1-year event-free survival (EFS) was 23% (standard error, SE = 9%) and 1-year overall survival (OS) was 64% (SE = 10%). Among the 14 eligible patients who enrolled on Stratum 2 and received protocol therapy, the 1-year EFS was 57% (SE = 13%) and 1-year OS was 93% (SE = 0.7%).
    CONCLUSIONS: Rapid central pathology review and molecular testing for eligibility was feasible. The protocol therapy including radiation, veliparib and temozolomide was well tolerated but failed to improve outcome compared to clinically and molecularly matched historical control cohorts treated with higher doses of alkylator chemotherapy.
    Keywords:  High grade glioma; clinical trial; glioblastoma; temozolomide; veliparib
    DOI:  https://doi.org/10.1093/neuonc/noae247
  9. Nature. 2024 Nov 20.
    Brain-penetrating molecule might offer a route to treat glioblastoma tumours.
    Mushtaq A Nengroo, Issam Ben-Sahra.
      
    Keywords:  Cancer; Medical research
    DOI:  https://doi.org/10.1038/d41586-024-03556-2
  10. Cancer Metab. 2024 Nov 19. 12(1): 35
    Glutaminolysis is associated with mitochondrial pathway activation and can be therapeutically targeted in glioblastoma.
    Kenji Miki, Mikako Yagi, Ryusuke Hatae, Ryosuke Otsuji, Takahiro Miyazaki, Katsuhiro Goto, Daiki Setoyama, Yutaka Fujioka, Yuhei Sangatsuda, Daisuke Kuga, Nayuta Higa, Tomoko Takajo, Yonezawa Hajime, Toshiaki Akahane, Akihide Tanimoto, Ryosuke Hanaya, Yuya Kunisaki, Takeshi Uchiumi, Koji Yoshimoto.
       BACKGROUND: Glioblastoma is an aggressive cancer that originates from abnormal cell growth in the brain and requires metabolic reprogramming to support tumor growth. Metabolic reprogramming involves the upregulation of various metabolic pathways. Although the activation of specific metabolic pathways in glioblastoma cell lines has been documented, the comprehensive profile of metabolic reprogramming and the role of each pathway in glioblastoma tissues in patients remain elusive.
    METHODS: We analyzed 38 glioblastoma tissues. As a test set, we examined 20 tissues from Kyushu University Hospital, focusing on proteins related to several metabolic pathways, including glycolysis, the one-carbon cycle, glutaminolysis, and the mitochondrial tricarboxylic acid cycle. Subsequently, we analyzed an additional 18 glioblastoma tissues from Kagoshima University Hospital as a validation set. We also validated our findings using six cell lines, including U87, LN229, U373, T98G, and two patient-derived cells.
    RESULTS: The levels of mitochondria-related proteins (COX1, COX2, and DRP1) were correlated with each other and with glutaminolysis-related proteins (GLDH and GLS1). Conversely, their expression was inversely correlated with that of glycolytic proteins. Notably, inhibiting the glutaminolysis pathway in cell lines with high GLDH and GLS1 expression proved effective in suppressing tumor growth.
    CONCLUSIONS: Our findings confirm that glioblastoma tissues can be categorized into glycolytic-dominant and mitochondrial-dominant types, as previously reported. The mitochondrial-dominant type is also glutaminolysis-dominant. Therefore, inhibiting the glutaminolysis pathway may be an effective treatment for mitochondrial-dominant glioblastoma.
    Keywords:  Glioblastoma; Glutaminolysis; Metabolic changes; Mitochondria
    DOI:  https://doi.org/10.1186/s40170-024-00364-0
  11. Am J Cancer Res. 2024 ;14(10): 5000-5010
    Generation and banking of patient-derived glioblastoma organoid and its application in cancer neuroscience.
    Li Zhou, Jian Yang, Shubei Wang, Pin Guo, Keman Liao, Zhonggang Shi, Jianyi Zhao, Shukai Lin, Ming Yang, Gang Cai, Qing Xia, Jianwei Ge, Jiayi Chen, Yingying Lin.
      Glioblastoma (GBM) is the most common and deadly tumor in the central nervous system. Although much has been done to optimize treatment options for GBM, the clinical prognosis is still very poor. The recent development of organoid models are emerging as cutting-edge tools in GBM research. However, the established and applications of organoid in cancer neuroscience are still elusive. In this study, we successfully established patient-derived GBM organoids (GBOs) with conserved pathological properties of parental GBM. Moreover, GBO-neuron co-culture system was also investigated and interactions between GFP labeled neurons and mCherry labeled GBOs have been observed. We further used an in-situ stereotaxic instrument to implant GBO into the brains of nude mice and established intracranial orthotopic GBM models based on these GBOs. Thus, we proposed a system to generate and bank patient-derived GBOs and verified its application in cancer neuroscience, which might be an important way to illustrate the mechanism of GBM.
    Keywords:  Glioblastoma; banking; cancer neuron science; generation; organoid
    DOI:  https://doi.org/10.62347/NSVA5836
  12. Proc Natl Acad Sci U S A. 2024 Nov 26. 121(48): e2416614121
    An E2 ubiquitin-conjugating enzyme links diubiquitinated H2B to H3K27M oncohistone function.
    Alan L Jiao, Erdem Sendinc, Barry M Zee, Felice Wallner, Yang Shi.
      The H3K27M oncogenic histone (oncohistone) mutation drives ~80% of incurable childhood brain tumors known as diffuse midline gliomas (DMGs). The major molecular feature of H3K27M mutant DMGs is a global loss of H3K27 trimethylation (H3K27me3), a phenotype conserved in Caenorhabditis elegans (C. elegans). Here, we perform unbiased genome-wide suppressor screens in C. elegans expressing H3K27M and isolate 20 suppressors, all of which at least partially restore H3K27me3. 19/20 suppressor mutations map to the same histone H3.3 gene in which the K27M mutation was originally introduced. Most of these create single amino acid substitutions between residues R26-Y54, which do not disrupt oncohistone expression. Rather, they are predicted to impair interactions with the Polycomb Repressive Complex 2 (PRC2) and are functionally conserved in human cells. Further, we mapped a single extragenic H3K27M suppressor to ubc-20, an E2 ubiquitin-conjugating enzyme, whose loss rescued H3K27me3 to nearly 50% wild-type levels despite continued oncohistone expression and chromatin incorporation. We demonstrate that ubc-20 is the major enzyme responsible for generating diubiquitinated histone H2B. Our study provides in vivo support for existing models of PRC2 inhibition via direct oncohistone contact and suggests that the effects of H3K27M may be modulated by H2B ubiquitination.
    Keywords:  C. elegans; H3K27M; Oncohistone; diffuse midline glioma; epigenetics
    DOI:  https://doi.org/10.1073/pnas.2416614121
  13. Neuro Oncol. 2024 Nov 22. pii: noae255. [Epub ahead of print]
    Inhibition of Mitochondrial Bioenergetics and Hypoxia to Radiosensitize Diffuse Intrinsic Pontine Glioma.
    Han Shen, Faiqa Mudassar, Shiyong Ma, Xingyu Wang, Sandy Nguyen, Neha Bal, Quy-Susan Huynh, Dongwei Wang, Cecilia Chang, Prunella Ing, Winny Varikatt, Joey Lai, Brian Gloss, Jeff Holst, Geraldine M O'Neill, Harriet Gee, Kristina M Cook, Eric Hau.
       BACKGROUND: Diffuse Intrinsic Pontine Gliomas (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are brain tumors that primarily affect children. Radiotherapy is the standard of care but only provides temporary symptomatic relief due to radioresistance. While hypoxia is a major driver of radioresistance in other tumors, there is no definitive evidence that DIPGs are hypoxic. DIPGs often contain histone mutations, which alter tumor metabolism and are also associated with radioresistance. Our objective was to identify the metabolic profiles of DIPG cells, detect hypoxia signatures, and uncover metabolism-linked mechanisms of radioresistance to improve tumor radiosensitivity.
    METHOD: Using DIPG models combined with clinical datasets, we examined mitochondrial metabolism and signatures of hypoxia. We explored DIPG reliance on mitochondrial metabolism using extracellular flux assays and targeted metabolomics. In vitro and in vivo models were used to explore the mechanisms of targeting mitochondrial bioenergetics and hypoxia for radiosensitization. Treatment-induced transcriptomics and metabolomics were also investigated.
    RESULTS: Comprehensive analyses of DIPG cells show signatures of enhanced oxidative phosphorylation (OXPHOS). We also identified increased expression of specific OXPHOS related genes and signatures of hypoxia gene expression in datasets obtained from DIPG patients. We found the presence of hypoxia in orthotopic mouse models bearing DIPG tumors. These findings enabled us to develop a proof-of-concept treatment strategy to enhance radiosensitivity of DIPGs in vitro and in animal models.
    CONCLUSION: DIPG cells rely on mitochondrial metabolism for growth, and targeting mitochondria disrupts bioenergetics, alleviates hypoxia, and enhances radiosensitivity. These findings warrant further exploration of OXPHOS inhibition as a radiosensitizing strategy for DIPG treatment.
    Keywords:  diffuse intrinsic pontine gliomas; hypoxia; mitochondria; radiotherapy
    DOI:  https://doi.org/10.1093/neuonc/noae255
  14. Nat Commun. 2024 Nov 19. 15(1): 10005
    Proteomic profiling of gliomas unveils immune and metabolism-driven subtypes with implications for anti-nucleotide metabolism therapy.
    Jinsen Zhang, Rui Sun, Yingying Lyu, Chaxian Liu, Ying Liu, Yuan Feng, Minjie Fu, Peter Jih Cheng Wong, Zunguo Du, Tianming Qiu, Yi Zhang, Dongxiao Zhuang, Zhiyong Qin, Yu Yao, Wei Zhu, Tiannan Guo, Wei Hua, Hui Yang, Ying Mao.
      Gliomas exhibit high heterogeneity and poor prognosis. Despite substantial progress has been made at the genomic and transcriptomic levels, comprehensive proteomic characterization and its implications remain largely unexplored. In this study, we perform proteomic profiling of gliomas using 343 formalin-fixed and paraffin-embedded tumor samples and 53 normal-appearing brain samples from 188 patients, integrating these data with genomic panel information and clinical outcomes. The proteomic analysis uncovers two distinct subgroups: Subgroup 1, the metabolic neural subgroup, enriched in metabolic enzymes and neurotransmitter receptor proteins, and Subgroup 2, the immune subgroup, marked by upregulation of immune and inflammatory proteins. These proteomic subgroups show significant differences in prognosis, tumorigenesis, microenvironment dysregulation, and potential therapeutics, highlighting the critical roles of metabolic and immune processes in glioma biology and patient outcomes. Through a detailed investigation of metabolic pathways guided by our proteomic findings, dihydropyrimidine dehydrogenase (DPYD) and thymidine phosphorylase (TYMP) emerge as potential prognostic biomarkers linked to the reprogramming of nucleotide metabolism. Functional validation in patient-derived glioma stem cells and animal models highlights nucleotide metabolism as a promising therapy target for gliomas. This integrated multi-omics analysis introduces a proteomic classification for gliomas and identifies DPYD and TYMP as key metabolic biomarkers, offering insights into glioma pathogenesis and potential treatment strategies.
    DOI:  https://doi.org/10.1038/s41467-024-54352-5
  15. Neuro Oncol. 2024 Nov 16. pii: noae234. [Epub ahead of print]
    Clinical and Genetic Markers of Vascular Toxicity in Glioblastoma Patients: Insights from NRG Oncology RTOG-0825.
    Joshua D Strauss, Mark R Gilbert, Minesh Mehta, Ang Li, Renke Zhou Ms, Melissa L Bondy, Erik P Sulman, Ying Yuan, Yanhong Liu, Elizabeth Vera, Merideth M Wendland, Volker W Stieber, Vinaykumar K Puduvalli, Serah Choi, Nina L Martinez, H Ian Robins, Grant K Hunter, Chi-Fan Lin, Vivian A Guedes, Melissa A Richard, Stephanie L Pugh, Terri S Armstrong, Michael E Scheurer.
       BACKGROUND: Glioblastoma (GBM) is an aggressive form of brain cancer in which treatment is associated with toxicities that can result in therapy discontinuation or death. This analysis investigated clinical and genetic markers of vascular toxicities in GBM patients during active treatment.
    METHODS: 591 Non-Hispanic White GBM patients with clinical data were included in the analysis from NRG RTOG-0825. Genome-wide association studies (GWAS) were performed from genotyped blood samples (N=367) by occurrence of thrombosis or hypertension (grade ≥2). A clinical prediction model was produced for each vascular toxicity. Significant GWAS variants were then added to the clinical model as a single nucleotide polymorphism (SNP) -dose effect variable to produce the final genetic models.
    RESULTS: Thrombosis and hypertension were experienced by 62 (11%) and 59 (10%) patients, respectively. Patients who experienced hypertension displayed improved survival over those without hypertension (median overall survival: 25.72 vs 15.47 months, p=0.002). The genetic model of thrombosis included corticosteroid use (OR: 7.13, p=0.02), absolute neutrophil count (OR: 1.008, p=0.19), body surface area (OR: 18.87, p=0.0008), and the SNP-dose effect (3 variants; OR: 3.79, p<.0001). The genetic model of hypertension included bevacizumab use (OR: 0.97, p=0.95) and the SNP-dose effect (6 variants; OR: 4.44, p<.0001).
    CONCLUSION: In this study, germline variants were superior in predicting hypertension than clinical variables alone. Additionally, corticosteroid use was a considerable risk factor for thrombosis. Future investigations should confirm the hazard of corticosteroid use on thrombosis and the impact of bevacizumab in other malignancies after accounting for the genetic risk of hypertension.
    Keywords:  bevacizumab; genome-wide association study; glioblastoma; hypertension; thrombosis
    DOI:  https://doi.org/10.1093/neuonc/noae234
  16. J Clin Invest. 2024 Nov 19. pii: e177824. [Epub ahead of print]
    Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.
    Kristen E Kay, Juyeun Lee, Ellen S Hong, Julia Beilis, Sahil Dayal, Emily R Wesley, Sofia Mitchell, Sabrina Z Wang, Daniel J Silver, Josephine Volovetz, Sarah Johnson, Mary McGraw, Matthew Grabowski, Tianyao Lu, Lutz Freytag, Vinod K Narayana, Saskia Freytag, Sarah A Best, James R Whittle, Zeneng Wang, Ofer Reizes, Jennifer S Yu, Stanley L Hazen, J Mark Brown, Defne Bayik, Justin Lathia.
      The glioblastoma (GBM) microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly impact the immune system, but the mechanisms driving these interactions are not completely clear. Here we demonstrate that the polyamine metabolite spermidine (SPD) is elevated in the GBM tumor microenvironment. Exogenous administration of SPD drives tumor aggressiveness in an immune-dependent manner in pre-clinical mouse models via reduction of CD8+ T cell frequency and reduced cytotoxic function. Knockdown of ornithine decarboxylase, the rate-limiting enzyme in spermidine synthesis, did not impact cancer cell growth in vitro but did result in extended survival. Furthermore, glioblastoma patients with a more favorable outcome had a significant reduction in spermidine compared to patients with a poor prognosis. Our results demonstrate that spermidine functions as a cancer cell-derived metabolite that drives tumor progression by reducing CD8+ T cell number and function.
    Keywords:  Adaptive immunity; Brain cancer; Immunology; Oncology; Polyamines
    DOI:  https://doi.org/10.1172/JCI177824
  17. Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdae169
    Biological and prognostic relevance of epigenetic regulatory genes in high-grade gliomas.
    Sonikpreet Aulakh, Joanne Xiu, Andrew Hinton, Sourat Darabi, Michael J Demeure, Soma Sengupta, Santosh Kesari, David M Ashley, Ashley Love Sumrall, Michael J Glantz, David Spetzler.
       Background: High-grade gliomas (HGGs) are the most aggressive type of gliomas and have the poorest outcomes. Chromatin remodeling (CR) genes have been implicated in multiple oncogenic pathways in numerous cancer types. In gliomagenesis, CR genes have been implicated in regulating the stemness of glioma cells, the tumor microenvironment (TME), and resistance to therapies.
    Methods: We performed molecular profiling of 4244 HGGs and evaluated associations of CR mutations with other cancer-related biomarkers, infiltration by immune cells, and immune gene expression. We also evaluated the association between CR mutations and survival in wild-type IDH HGG patients.
    Results: Nearly 10% of HGGs carry mutations in CR genes, with a higher prevalence (15%) in HGGs with IDH mutations. Analysis of cooccurrence with other biomarkers revealed that CR-mutated HGGs possess favorable genetic alterations which may have prognostic value. CR-mutated HGGs with wild-type IDH demonstrated colder TME and worse OS overall compared to the CR-wild-type HGGs.
    Conclusions: Our study reveals the prognostic effects of CR mutations in HGG and points to several biomarker candidates that could suggest sensitivity to emerging therapeutic strategies.
    Keywords:  chromatin remodeling; clinical oncology; glioma; molecular oncology
    DOI:  https://doi.org/10.1093/noajnl/vdae169
  18. Clin Transl Med. 2024 Nov;14(11): e70030
    An AMP-activated protein kinase-PGC-1α axis mediates metabolic plasticity in glioblastoma.
    Benedikt Sauer, Jan Kueckelhaus, Nadja I Lorenz, Süleyman Bozkurt, Dorothea Schulte, Jan-Béla Weinem, Mohaned Benzarti, Johannes Meiser, Hans Urban, Giulia Villa, Patrick N Harter, Christian Münch, Johannes Rieger, Joachim P Steinbach, Dieter Henrik Heiland, Michael W Ronellenfitsch.
      Glioblastoma, the most frequent primary malignant brain tumour in adults, is characterised by profound yet dynamic hypoxia and nutrient depletion. To sustain survival and proliferation, tumour cells are compelled to acquire metabolic plasticity with the induction of adaptive metabolic programs. Here, we interrogated the pathways necessary to enable processing of nutrients other than glucose. We employed genetic approaches (stable/inducible overexpression, CRISPR/Cas9 knockout), pharmacological interventions with a novel inhibitor of AMP-activated protein kinase (AMPK) in glioblastoma cell culture systems and a proteomic approach to investigate mechanisms of metabolic plasticity. Moreover, a spatially resolved multiomic analysis was employed to correlate the gene expression pattern of PGC-1α with the local metabolic and genetic architecture in human glioblastoma tissue sections. A switch from glucose to alternative nutrients triggered an activation of AMPK, which in turn activated PGC-1α-dependent adaptive programs promoting mitochondrial metabolism. This sensor-effector mechanism was essential for metabolic plasticity with both functional AMPK and PGC-1α necessary for survival and growth of cells under nonglucose nutrient sources. In human glioblastoma tissue specimens, PGC-1α-expression correlated with nonhypoxic tumour niches defining a specific metabolic compartment. Our findings reveal a cell-intrinsic nutrient sensing and switching mechanism. The exposure to alternative fuels triggers a starvation signal that subsequently is passed on via AMPK and PGC-1α to induce adaptive programs necessary for broader spectrum nutrient metabolism. The integration of spatially resolved transcriptomic data confirms the relevance of PGC-1α especially in nonhypoxic tumour regions. Thus, the AMPK-PGC-1α axis is a candidate for therapeutic inhibition in glioblastoma. KEY POINTS/HIGHLIGHTS: AMPK activation induces PGC-1α expression in glioblastoma during nutrient scarcity. PGC-1α enables metabolic plasticity by facilitating metabolism of alternative nutrients in glioblastoma. PGC-1α expression is inversely correlated with hypoxic tumour regions in human glioblastomas.
    Keywords:  AMP‐activated protein kinase; PGC‐1α; PPARGC1A; glioblastoma; hypoxia; metabolic plasticity; tumour microenvironment
    DOI:  https://doi.org/10.1002/ctm2.70030
  19. Neuro Oncol. 2024 Nov 21. pii: noae248. [Epub ahead of print]
    G-quadruplex stabilizer CX-5461 effectively combines with radiotherapy to target ATRX-deficient malignant glioma.
    Sharvari Dharmaiah, Prit Benny Malgulwar, William E Johnson, Brandon A Chen, Vladislav Sharin, Benjamin T Whitfield, Christian Alvarez, Vasudev Tadimeti, Ahsan S Farooqi, Jason T Huse.
       BACKGROUND: Inactivation of α-thalassaemia/mental retardation X-linked (ATRX) represents a defining molecular feature in large subsets of malignant glioma. ATRX deficiency gives rise to abnormal G-quadruplex (G4) DNA secondary structures, enhancing replication stress and genomic instability. Building on earlier work, we evaluated the extent to which pharmacological G4 stabilization selectively enhances DNA damage and cell death in ATRX-deficient preclinical glioma models.
    METHODS: Using the G4 stabilizer CX-5461, we treated patient-derived glioma stem cells (GSCs) in vitro and GSC flank and intracranial murine xenografts in vivo to evaluate efficacy as both a single agent and in combination with ionizing radiation (IR), the latter a central element of current treatment standards.
    RESULTS: CX-5461 promoted dose-sensitive lethality in ATRX-deficient GSCs relative to ATRX-intact controls. Mechanistic studies revealed that CX-5461 disrupted histone variant H3.3 deposition, enhanced replication stress and DNA damage, activated p53-independent apoptosis, and induced G2/M arrest to a greater extent in ATRX-deficient GSCs than in ATRX-intact counterparts. These data were corroborated in vivo, where CX-5461/IR treatment profoundly delayed tumor growth and prolonged survival in mice bearing ATRX-deficient flank xenografts. Histopathological analyses revealed decreased proliferation, increased apoptosis, and significant G4 induction, replication stress, and DNA damage in CX-5461-treated tumors, both alone and in combination with IR. Finally, despite suboptimal blood-brain-barrier penetration, systemic CX-5461 treatment induced tangible pharmacodynamic effects in ATRX-deficient intracranial GSC models.
    CONCLUSIONS: In totality, our work substantively demonstrates efficacy and defines mechanisms of action for G4 stabilization as a novel therapeutic strategy targeting ATRX-deficient malignant glioma, laying the groundwork for clinical translation.
    Keywords:  ATRX; CX-5461; G-quadruplex; glioma; radiation
    DOI:  https://doi.org/10.1093/neuonc/noae248
  20. Cancer Res. 2024 Nov 21.
    PTBP1 Lactylation Promotes Glioma Stem Cell Maintenance through PFKFB4-Driven Glycolysis.
    Zijian Zhou, Xianyong Yin, Hao Sun, Jiaze Lu, Yuming Li, Yang Fan, Peiwen Lv, Min Han, Jing Wu, Shengjie Li, Zihao Liu, Hongbo Zhao, Haohan Sun, Hao Fan, Shan Wang, Tao Xin.
      Longstanding evidence implicates glioma stem cells (GSCs) as the major driver for glioma propagation and recurrence. GSCs have a distinctive metabolic landscape characterized by elevated glycolysis. Lactate accumulation resulting from enhanced glycolytic activity can drive lysine lactylation to regulate protein functions, suggesting that elucidating the lactylation landscape in GSCs could provide insights into glioma biology. Herein, we demonstrated that global lactylation was significantly elevated in GSCs compared to differentiated glioma cells (DGCs). PTBP1, a central regulator of RNA processing, was hyperlactylated in GSCs, and SIRT1 induced PTBP1 delactylation. PTBP1-K436 lactylation supported glioma progression and GSC maintenance. Mechanistically, K436 lactylation inhibited PTBP1 proteasomal degradation by attenuating the interaction with TRIM21. Moreover, PTBP1 lactylation enhanced its RNA-binding capacity and facilitated PFKFB4 mRNA stabilization, which further increased glycolysis. Together, these findings uncovered a lactylation-mediated mechanism in GSCs driven by metabolic reprogramming that induces aberrant epigenetic modifications to further stimulate glycolysis, resulting in a vicious cycle to exacerbate tumorigenesis.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-1412
  21. Neuro Oncol. 2024 Nov 18. pii: noae228. [Epub ahead of print]
    Alternative lengthening of telomere-based immortalization renders H3G34R -mutant diffuse hemispheric glioma hypersensitive to PARP inhibitor combination regimens.
    Anna Laemmerer, Christian Lehmann, Lisa Mayr, Katharina Bruckner, Lisa Gabler, Daniel Senfter, Philipp Meyer, Theresa Balber, Christine Pirker, Carola N Jaunecker, Dominik Kirchhofer, Petra Vician, Michelle Griesser, Sabine Spiegl-Kreinecker, Maria T Schmook, Tatjana Traub-Weidinger, Peter Kuess, Franziska Eckert, Aniello Federico, Sibylle Madlener, Natalia Stepien, Bernhard Robl, Alicia Baumgartner, Johannes A Hainfellner, Karin Dieckmann, Christian Dorfer, Karl Roessler, Nina S Corsini, Klaus Holzmann, Wolfgang M Schmidt, Andreas Peyrl, Amedeo A Azizi, Christine Haberler, Alexander Beck, Stefan M Pfister, Julia Schueler, Daniela Loetsch-Gojo, Jürgen A Knoblich, Walter Berger, Johannes Gojo.
       BACKGROUND: Diffuse hemispheric glioma, H3G34R/V-mutant (DHG-H3G34) is characterized by poor prognosis and lack of effective treatment options. DHG-H3G34R further harbor deactivation of Alpha-Thalassemia/Mental Retardation Syndrome X-linked protein (ATRX; DHG-H3G34R_ATRX) suggesting a unique interaction of these two oncogenic alterations. In this study, we dissect their cell biological interplay, investigate the impact on telomere stabilization and, consequently, validate a targeted therapy approach.
    METHODS: We characterized patient-derived primary pediatric high-grade glioma (pHGG) models for telomere-maintenance mechanisms, DNA damage stress (including protein expression, pH2AX/Rad51 foci, cell-cycle arrest) and their sensitivity towards poly-ADP polymerase inhibitor (PARPi) combinations. Human induced pluripotent stem cells (iPSCs) were used for modelling the disease. The anticancer activity of PARPi combinations in vivo was studied in Chorioallantoic Membrane (CAM) and orthotopic in vivo experiments. Finally, we treated a DHG-H3G34R_ATRX patient with a PARPi combination therapy.
    RESULTS: We elaborate that alternative lengthening of telomeres (ALT) is a key characteristic of DHG-H3G34R_ATRX. A dominant cooperative effect between H3G34R and ATRX loss in ALT activation also became apparent in iPSCs, which endogenously exert telomerase activity. In both, patient-derived DHG-H3G34R_ATRX models and H3G34R+/ATRX- iPSCs, the ALT phenotype was associated with increased basal DNA damage stress, mediating synergistic susceptibility towards PARPi (talazoparib, niraparib) combinations with topoisomerase-I inhibitors (topotecan, irinotecan). In a first-of-its-kind case, treatment of a DHG-H3G34R_ATRX patient with the brain-penetrant PARP inhibitor niraparib and topotecan resulted in a significant tumor reduction.
    CONCLUSION: Our preclinical and clinical data strongly support the further development of PARPis together with DNA damage stress-inducing treatment regimens for DHG-H3G34R_ATRX.
    Keywords:  ATRX; DNA damage; Diffuse hemispheric glioma; H3G34R; PARP inhibitor
    DOI:  https://doi.org/10.1093/neuonc/noae228
  22. Nat Commun. 2024 Nov 21. 15(1): 10089
    Integrated molecular and functional characterization of the intrinsic apoptotic machinery identifies therapeutic vulnerabilities in glioma.
    Elizabeth G Fernandez, Wilson X Mai, Kai Song, Nicholas A Bayley, Jiyoon Kim, Henan Zhu, Marissa Pioso, Pauline Young, Cassidy L Andrasz, Dimitri Cadet, Linda M Liau, Gang Li, William H Yong, Fausto J Rodriguez, Scott J Dixon, Andrew J Souers, Jingyi Jessica Li, Thomas G Graeber, Timothy F Cloughesy, David A Nathanson.
      Genomic profiling often fails to predict therapeutic outcomes in cancer. This failure is, in part, due to a myriad of genetic alterations and the plasticity of cancer signaling networks. Functional profiling, which ascertains signaling dynamics, is an alternative method to anticipate drug responses. It is unclear whether integrating genomic and functional features of solid tumours can provide unique insight into therapeutic vulnerabilities. We perform combined molecular and functional characterization, via BH3 profiling of the intrinsic apoptotic machinery, in glioma patient samples and derivative models. We identify that standard-of-care therapy rapidly rewires apoptotic signaling in a genotype-specific manner, revealing targetable apoptotic vulnerabilities in gliomas containing specific molecular features (e.g., TP53 WT). However, integration of BH3 profiling reveals high mitochondrial priming is also required to induce glioma apoptosis. Accordingly, a machine-learning approach identifies a composite molecular and functional signature that best predicts responses of diverse intracranial glioma models to standard-of-care therapies combined with ABBV-155, a clinical drug targeting intrinsic apoptosis. This work demonstrates how complementary functional and molecular data can robustly predict therapy-induced cell death.
    DOI:  https://doi.org/10.1038/s41467-024-54138-9
  23. Nat Cancer. 2024 Nov 21.
    Evolving cell states and oncogenic drivers during the progression of IDH-mutant gliomas.
    Jingyi Wu, L Nicolas Gonzalez Castro, Sofia Battaglia, Chadi A El Farran, Joshua P D'Antonio, Tyler E Miller, Mario L Suvà, Bradley E Bernstein.
      Isocitrate dehydrogenase (IDH) mutants define a class of gliomas that are initially slow-growing but inevitably progress to fatal disease. To characterize their malignant cell hierarchy, we profiled chromatin accessibility and gene expression across single cells from low-grade and high-grade IDH-mutant gliomas and ascertained their developmental states through a comparison to normal brain cells. We provide evidence that these tumors are initially fueled by slow-cycling oligodendrocyte progenitor cell-like cells. During progression, a more proliferative neural progenitor cell-like population expands, potentially through partial reprogramming of 'permissive' chromatin in progenitors. This transition is accompanied by a switch from methylation-based drivers to genetic ones. In low-grade IDH-mutant tumors or organoids, DNA hypermethylation appears to suppress interferon (IFN) signaling, which is induced by IDH or DNA methyltransferase 1 inhibitors. High-grade tumors frequently lose this hypermethylation and instead acquire genetic alterations that disrupt IFN and other tumor-suppressive programs. Our findings explain how these slow-growing tumors may progress to lethal malignancies and have implications for therapies that target their epigenetic underpinnings.
    DOI:  https://doi.org/10.1038/s43018-024-00865-3
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