bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2023–01–22
thirteen papers selected by
Oltea Sampetrean, Keio University
  1. Immune checkpoint blockade in glioblastoma: from tumor heterogeneity to personalized treatment.
  2. Impact of epigenetic reprogramming on antitumor immune responses in glioma.
  3. Artificial intelligence-based locoregional markers of brain peritumoral microenvironment.
  4. Lysine-specific histone demethylase 1A (KDM1A/LSD1) inhibition attenuates DNA double strand break repair and augments efficacy of temozolomide in glioblastoma.
  5. Targeting Microglial Metabolic Rewiring Synergizes with Immune Checkpoint Blockade Therapy for Glioblastoma.
  6. Clinico-pathological and epigenetic heterogeneity of diffuse gliomas with FGFR3::TACC3 fusion.
  7. Targeting de novo lipid synthesis induces lipotoxicity and impairs DNA damage repair in glioblastoma mouse models.
  8. Stem cell-nanomedicine system as a theranostic bio-gadolinium agent for targeted neutron capture cancer therapy.
  9. Liquid biopsy of cerebrospinal fluid enables selective profiling of glioma molecular subtypes at first clinical presentation.
  10. Challenges and Opportunities for Clinical Trials in Patients With Glioma.
  11. Protein kinase B (PKB/AKT) protects IDH-mutated glioma from ferroptosis via Nrf2.
  12. CIC reduces xCT/SLC7A11 expression and glutamate release in glioma.
  13. Blood-Borne Myeloid Cell Loss of MHCII Drives Cytotoxic T-cell Dysfunction.
  1. J Clin Invest. 2023 Jan 17. pii: e163447. [Epub ahead of print]133(2):
    Immune checkpoint blockade in glioblastoma: from tumor heterogeneity to personalized treatment.
    Víctor A Arrieta, Crismita Dmello, Daniel J McGrail, Daniel J Brat, Catalina Lee-Chang, Amy B Heimberger, Dhan Chand, Roger Stupp, Adam M Sonabend.
      Immune checkpoint blockade (ICB) has revolutionized modern cancer therapy, arousing great interest in the neuro-oncology community. While several reports show that subsets of patients with glioma exhibit durable responses to immunotherapy, the efficacy of this treatment has not been observed for unselected patient populations, preventing its broad clinical implementation for gliomas and glioblastoma (GBM). To exploit the maximum therapeutic potential of ICB for patients with glioma, understanding the different aspects of glioma-related tumor immune responses is of critical importance. In this Review, we discuss contributing factors that distinguish subsets of patients with glioma who may benefit from ICB. Specifically, we discuss (a) the complex interaction between the tumor immune microenvironment and glioma cells as a potential influence on immunotherapy responses; (b) promising biomarkers for responses to immune checkpoint inhibitors; and (c) the potential contributions of peripheral immune cells to therapeutic responses.
    DOI:  https://doi.org/10.1172/JCI163447
  2. J Clin Invest. 2023 Jan 17. pii: e163450. [Epub ahead of print]133(2):
    Impact of epigenetic reprogramming on antitumor immune responses in glioma.
    Brandon L McClellan, Santiago Haase, Felipe J Nunez, Mahmoud S Alghamri, Ali A Dabaja, Pedro R Lowenstein, Maria G Castro.
      Epigenetic remodeling is a molecular hallmark of gliomas, and it has been identified as a key mediator of glioma progression. Epigenetic dysregulation contributes to gliomagenesis, tumor progression, and responses to immunotherapies, as well as determining clinical features. This epigenetic remodeling includes changes in histone modifications, chromatin structure, and DNA methylation, all of which are driven by mutations in genes such as histone 3 genes (H3C1 and H3F3A), isocitrate dehydrogenase 1/2 (IDH1/2), α-thalassemia/mental retardation, X-linked (ATRX), and additional chromatin remodelers. Although much of the initial research primarily identified how the epigenetic aberrations impacted glioma progression by solely examining the glioma cells, recent studies have aimed at establishing the role of epigenetic alterations in shaping the tumor microenvironment (TME). In this review, we discuss the mechanisms by which these epigenetic phenomena in glioma remodel the TME and how current therapies targeting epigenetic dysregulation affect the glioma immune response and therapeutic outcomes. Understanding the link between epigenetic remodeling and the glioma TME provides insights into the implementation of epigenetic-targeting therapies to improve the antitumor immune response.
    DOI:  https://doi.org/10.1172/JCI163450
  3. Sci Rep. 2023 Jan 18. 13(1): 963
    Artificial intelligence-based locoregional markers of brain peritumoral microenvironment.
    Zahra Riahi Samani, Drew Parker, Hamed Akbari, Ronald L Wolf, Steven Brem, Spyridon Bakas, Ragini Verma.
      In malignant primary brain tumors, cancer cells infiltrate into the peritumoral brain structures which results in inevitable recurrence. Quantitative assessment of infiltrative heterogeneity in the peritumoral region, the area where biopsy or resection can be hazardous, is important for clinical decision making. Here, we derive a novel set of Artificial intelligence (AI)-based markers capturing the heterogeneity of tumor infiltration, by characterizing free water movement restriction in the peritumoral region using Diffusion Tensor Imaging (DTI)-based free water volume fraction maps. We leverage the differences in the peritumoral region of metastasis and glioblastomas, the former consisting of vasogenic versus the latter containing infiltrative edema, to extract a voxel-wise deep learning-based peritumoral microenvironment index (PMI). Descriptive characteristics of locoregional hubs of uniformly high PMI values are then extracted as AI-based markers to capture distinct aspects of infiltrative heterogeneity. The proposed markers are utilized to stratify patients' survival and IDH1 mutation status on a population of 275 adult-type diffuse gliomas (CNS WHO grade 4). Our results show significant differences in the proposed markers between patients with different overall survival and IDH1 mutation status (t test, Wilcoxon rank sum test, linear regression; p < 0.01). Clustering of patients using the proposed markers reveals distinct survival groups (logrank; p < 10-5, Cox hazard ratio = 1.82; p < 0.005). Our findings provide a panel of markers as surrogates of infiltration that might capture novel insight about underlying biology of peritumoral microstructural heterogeneity, providing potential biomarkers of prognosis pertaining to survival and molecular stratification, with applicability in clinical decision making.
    DOI:  https://doi.org/10.1038/s41598-022-26448-9
  4. Neuro Oncol. 2023 Jan 18. pii: noad018. [Epub ahead of print]
    Lysine-specific histone demethylase 1A (KDM1A/LSD1) inhibition attenuates DNA double strand break repair and augments efficacy of temozolomide in glioblastoma.
    Salvador Alejo, Bridgitte E Palacios, Prabhakar Pitta Venkata, Yi He, Wenjing Li, Jessica D Johnson, Chen Yihong, Sridharan Jayamohan, Uday P Pratap, Kyra Clarke, Yi Zou, Yingli Lv, Korri Weldon, Suryavathi Viswanadhapalli, Zhao Lai, Zhenqing Ye, Yidong Chen, Andrea R Gilbert, Takayoshi Suzuki, Rajeshwar R Tekmal, Weixing Zhao, Siyuan Zheng, Ratna K Vadlamudi, Andrew J Brenner, Gangadhara R Sareddy.
       BACKGROUND: Efficient DNA repair in response to standard chemo and radiation therapies often contribute to GBM therapy resistance. Understanding the mechanisms of therapy resistance and identifying the drugs that enhance the therapeutic efficacy of standard therapies may extend the survival of GBM patients. In this study, we investigated the role of KDM1A/LSD1 in DNA double strand break (DSB) repair and combination of KDM1A inhibitor and TMZ in vitro and in vivo using patient derived GSCs.
    METHODS: Brain-bioavailability of the KDM1A inhibitor (NCD38) was established using LS-MS/MS. Effect of combination of KDM1A knockdown or inhibition with TMZ was studied using cell viability and self-renewal assays. Mechanistic studies were conducted using CUT&Tag-seq, RNA-seq, RT-qPCR, Western blot, HR and NHEJ reporter, immunofluorescence, and comet assays. Orthotopic murine models were used to study efficacy in vivo.
    RESULTS: TCGA analysis showed KDM1A is highly expressed in TMZ treated GBM patients. Knockdown or knockout or inhibition of KDM1A enhanced TMZ efficacy in reducing the viability and selfrenewal of GSCs. Pharmacokinetic studies established that NCD38 readily crosses the BBB. CUT&Tag-seq studies showed that KDM1A is enriched at the promoters of DNA repair genes and RNA-seq studies confirmed that KDM1A inhibition reduced their expression. Knockdown or inhibition of KDM1A attenuated HR and NHEJ-mediated DNA repair capacity and enhanced TMZ mediated DNA damage. Combination of KDM1A knockdown or inhibition and TMZ treatment significantly enhanced survival of tumor bearing mice.
    CONCLUSIONS: Our results provide evidence that KDM1A inhibition sensitizes GBM to TMZ via attenuation of DNA DSB repair pathways.
    Keywords:  DNA repair; KDM1A/LSD1; glioblastoma; glioma stem cells; temozolomide
    DOI:  https://doi.org/10.1093/neuonc/noad018
  5. Cancer Discov. 2023 Jan 17. pii: CD-22-0455. [Epub ahead of print]
    Targeting Microglial Metabolic Rewiring Synergizes with Immune Checkpoint Blockade Therapy for Glioblastoma.
    Zengpanpan Ye, Xiaolin Ai, Kailin Yang, Zhengnan Yang, Fan Fei, Xiaoling Liao, Zhixin Qiu, Ryan C Gimple, Huairui Yuan, Hao Huang, Yanqiu Gong, Chaoxin Xiao, Jing Yue, Liang Huang, Olivier Saulnier, Wei Wang, Peidong Zhang, Lunzhi Dai, Xin Wang, Xiuxing Wang, Young Ha Ahn, Chao You, Jianguo Xu, Xiaoxiao Wan, Michael D Taylor, Linjie Zhao, Jeremy N Rich, Shengtao Zhou.
      Glioblastoma (GBM) constitutes the most lethal primary brain tumor for which immunotherapy has provided limited benefit. The unique brain immune landscape is reflected in a complex tumor immune microenvironment (TIME) in GBM. Here, single cell sequencing of the GBM TIME revealed that microglia were under severe oxidative stress, which induced nuclear receptor subfamily 4 group A member 2 (NR4A2)-dependent transcriptional activity in microglia. Heterozygous Nr4a2 (Nr4a2+/-) or microglia-specific Nr4a2 (Nr4a2fl/flCx3cr1cre) genetic targeting reshaped microglia plasticity in vivo by reducing alternatively activated microglia and enhancing antigen presentation capacity for CD8+ T cells in GBM. In microglia, NR4A2 activated squalene monooxygenase (SQLE) to dysregulate cholesterol homeostasis. Pharmacological NR4A2 inhibition attenuated the pro-tumorigenic TIME, and targeting the NR4A2 or SQLE enhanced therapeutic efficacy of immune checkpoint blockade in vivo. Collectively, oxidative stress promotes tumor growth through NR4A2-SQLE activity in microglia, informing novel immune therapy paradigms in brain cancer.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-0455
  6. Acta Neuropathol Commun. 2023 Jan 16. 11(1): 14
    Clinico-pathological and epigenetic heterogeneity of diffuse gliomas with FGFR3::TACC3 fusion.
    Biopathology RENOCLIP-LOC network
       BACKGROUND: Gliomas with FGFR3::TACC3 fusion mainly occur in adults, display pathological features of glioblastomas (GB) and are usually classified as glioblastoma, IDH-wildtype. However, cases demonstrating pathological features of low-grade glioma (LGG) lead to difficulties in classification and clinical management. We report a series of 8 GB and 14 LGG with FGFR3:TACC3 fusion in order to better characterize them.
    METHODS: Centralized pathological examination, search for TERT promoter mutation and DNA-methylation profiling were performed in all cases. Search for prognostic factors was done by the Kaplan-Meir method.
    RESULTS: TERT promoter mutation was recorded in all GB and 6/14 LGG. Among the 7 cases with a methylation score > 0.9 in the classifier (v12.5), 2 were classified as glioblastoma, 4 as ganglioglioma (GG) and 1 as dysembryoplastic neuroepithelial tumor (DNET). t-SNE analysis showed that the 22 cases clustered into three groups: one included 12 cases close to glioblastoma, IDH-wildtype methylation class (MC), 5 cases each clustered with GG or DNET MC but none with PLNTY MC. Unsupervised clustering analysis revealed four groups, two of them being clearly distinct: 5 cases shared age (< 40), pathological features of LGG, lack of TERT promoter mutation, FGFR3(Exon 17)::TACC3(Exon 10) fusion type and LGG MC. In contrast, 4 cases shared age (> 40), pathological features of glioblastoma, and were TERT-mutated. Relevant factors associated with a better prognosis were age < 40 and lack of TERT promoter mutation.
    CONCLUSION: Among gliomas with FGFR3::TACC3 fusion, age, TERT promoter mutation, pathological features, DNA-methylation profiling and fusion subtype are of interest to determine patients' risk.
    Keywords:  2021 WHO classification of CNS tumours; DNA-methylation profiling; FGFR3:TACC3 fusion; Glioblastoma; Pediatric low grade glioma
    DOI:  https://doi.org/10.1186/s40478-023-01506-z
  7. Sci Transl Med. 2023 Jan 18. 15(679): eabq6288
    Targeting de novo lipid synthesis induces lipotoxicity and impairs DNA damage repair in glioblastoma mouse models.
    Katharina M Eyme, Alessandro Sammarco, Roshani Jha, Hayk Mnatsakanyan, Caline Pechdimaljian, Litia Carvalho, Rudolph Neustadt, Charlotte Moses, Ahmad Alnasser, Daniel F Tardiff, Baolong Su, Kevin J Williams, Steven J Bensinger, Chee Yeun Chung, Christian E Badr.
      Deregulated de novo lipid synthesis (DNLS) is a potential druggable vulnerability in glioblastoma (GBM), a highly lethal and incurable cancer. Yet the molecular mechanisms that determine susceptibility to DNLS-targeted therapies remain unknown, and the lack of brain-penetrant inhibitors of DNLS has prevented their clinical evaluation as GBM therapeutics. Here, we report that YTX-7739, a clinical-stage inhibitor of stearoyl CoA desaturase (SCD), triggers lipotoxicity in patient-derived GBM stem-like cells (GSCs) and inhibits fatty acid desaturation in GSCs orthotopically implanted in mice. When administered as a single agent, or in combination with temozolomide (TMZ), YTX-7739 showed therapeutic efficacy in orthotopic GSC mouse models owing to its lipotoxicity and ability to impair DNA damage repair. Leveraging genetic, pharmacological, and physiological manipulation of key signaling nodes in gliomagenesis complemented with shotgun lipidomics, we show that aberrant MEK/ERK signaling and its repression of the energy sensor AMP-activated protein kinase (AMPK) primarily drive therapeutic vulnerability to SCD and other DNLS inhibitors. Conversely, AMPK activation mitigates lipotoxicity and renders GSCs resistant to the loss of DNLS, both in culture and in vivo, by decreasing the saturation state of phospholipids and diverting toxic lipids into lipid droplets. Together, our findings reveal mechanisms of metabolic plasticity in GSCs and provide a framework for the rational integration of DNLS-targeted GBM therapies.
    DOI:  https://doi.org/10.1126/scitranslmed.abq6288
  8. Nat Commun. 2023 Jan 18. 14(1): 285
    Stem cell-nanomedicine system as a theranostic bio-gadolinium agent for targeted neutron capture cancer therapy.
    Yen-Ho Lai, Chia-Yu Su, Hung-Wei Cheng, Chao-Yi Chu, Long-Bin Jeng, Chih-Sheng Chiang, Woei-Cherng Shyu, San-Yuan Chen.
      The potential clinical application of gadolinium-neutron capture therapy (Gd-NCT) for glioblastoma multiforme (GBM) treatment has been compromised by the fast clearance and nonspecific biodistribution of gadolinium-based agents. We have developed a stem cell-nanoparticle system (SNS) to actively target GBM for advanced Gd-NCT by magnetizing umbilical cord mesenchymal stem cells (UMSCs) using gadodiamide-concealed magnetic nanoparticles (Gd-FPFNP). Nanoformulated gadodiamide shielded by a dense surface composed of fucoidan and polyvinyl alcohol demonstrates enhanced cellular association and biocompatibility in UMSCs. The SNS preserves the ability of UMSCs to actively penetrate the blood brain barrier and home to GBM and, when magnetically navigates by an external magnetic field, an 8-fold increase in tumor-to-blood ratio is achieved compared with clinical data. In an orthotopic GBM-bearing rat model, using a single dose of irradiation and an ultra-low gadolinium dose (200 μg kg-1), SNS significantly attenuates GBM progression without inducing safety issues, prolonging median survival 2.5-fold compared to free gadodiamide. The SNS is a cell-based delivery system that integrates the strengths of cell therapy and nanotechnology, which provides an alternative strategy for the treatment of brain diseases.
    DOI:  https://doi.org/10.1038/s41467-023-35935-0
  9. Clin Cancer Res. 2023 Jan 17. pii: CCR-22-2903. [Epub ahead of print]
    Liquid biopsy of cerebrospinal fluid enables selective profiling of glioma molecular subtypes at first clinical presentation.
    Francesca Orzan, Francesca De Bacco, Elisabetta Lazzarini, Giovanni Crisafulli, Alessandra Gasparini, Angelo Dipasquale, Ludovic Barault, Marco Macagno, Pasquale Persico, Federico Pessina, Beatrice Bono, Laura Giordano, Pietro Zeppa, Antonio Melcarne, Paola Cassoni, Diego Garbossa, Armando Santoro, Paolo M Comoglio, Stefano Indraccolo, Matteo Simonelli, Carla Boccaccio.
       PURPOSE: Current glioma diagnostic guidelines call for molecular profiling to stratify patients into prognostic and treatment subgroups. In case the tumor tissue is inaccessible, cerebrospinal fluid (CSF) has been proposed as a reliable tumor DNA source for liquid biopsy. We prospectively investigated the use of CSF for molecular characterization of newly diagnosed gliomas.
    EXPERIMENTAL DESIGN: We recruited two cohorts of newly diagnosed glioma patients, one (n=45) providing CSF collected in proximity of the tumor, the other (n=39) CSF collected by lumbar puncture. Both cohorts provided tumor tissues by surgery concomitant with CSF sampling. DNA samples retrieved from CSF and matched tumors were systematically characterized and compared by comprehensive (NGS) or targeted (ddPCR) methodologies. Conventional and molecular diagnosis outcomes were compared.
    RESULTS: We report that tumor DNA is abundant in CSF close to the tumor, but scanty and mostly below NGS sensitivity threshold in CSF from lumbar puncture. Indeed, tumor DNA is 15 mostly released by cells invading liquoral spaces, generating a gradient that attenuates by departing from the tumor. Nevertheless, in >60% of lumbar puncture CSF samples, tumor DNA is sufficient to assess a selected panel of genetic alterations (IDH and TERT promoter mutations, EGFR amplification, CDKN2A/B deletion: ITEC protocol) and MGMT methylation that, combined with imaging, enable tissue-agnostic identification of main glioma molecular subtypes.
    CONCLUSIONS: This study shows potentialities and limitations of CSF liquid biopsy in achieving molecular characterization of gliomas at first clinical presentation and proposes a protocol to maximize diagnostic information retrievable from CSF DNA.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-2903
  10. JAMA Neurol. 2023 Jan 17.
    Challenges and Opportunities for Clinical Trials in Patients With Glioma.
    L Nicolas Gonzalez Castro, Isabel C Arrillaga-Romany, Tracy T Batchelor.
      
    DOI:  https://doi.org/10.1001/jamaneurol.2022.4924
  11. Clin Cancer Res. 2023 Jan 17. pii: CCR-22-3179. [Epub ahead of print]
    Protein kinase B (PKB/AKT) protects IDH-mutated glioma from ferroptosis via Nrf2.
    Yang Liu, Fu-Ju Chou, Fengchao Lang, Meili Zhang, Hua Song, Wei Zhang, Dionne L Davis, Nicole J Briceno, Yang Zhang, Patrick J Cimino, Kareem A Zaghloul, Mark R Gilbert, Terri S Armstrong, Chunzhang Yang.
       PURPOSE: Mutations of the isocitrate dehydrogenase (IDH) gene are common genetic mutations in human malignancies. Increasing evidence indicates that IDH mutations play critical roles in malignant transformation and progression. However, the therapeutic options for IDH-mutated cancers remain limited. In this study, the investigation of patient cohorts revealed that the phosphatidylinositol-3 kinase (PI3Ks)/protein kinase B (AKT) signaling pathways were enhanced in IDH-mutated cancer cells.
    EXPERIMENTAL DESIGN: In this study, we investigated the gene expression profile in IDH-mutated cells using RNA sequencing after the depletion of AKT. Gene set enrichment analysis (GSEA) and pathway enrichment analysis were used to discover altered molecular pathways due to AKT depletion. We further investigated the therapeutic effect of the AKT inhibitor, Ipatasertib, combined with Temozolomide (TMZ) in cell lines and preclinical animal models.
    RESULTS: GSEA and pathway enrichment analysis indicated that the PI3K/AKT pathway significantly correlated with Nrf2-guided gene expression and ferroptosis-related pathways. Mechanistically, AKT suppresses the activity of GSK3b and stabilizes Nrf2. Moreover, inhibition of AKT activity with ipatasertib synergizes with the genotoxic agent temozolomide, leading to overwhelming ferroptotic cell death in IDH-mutated cancer cells. The preclinical animal model confirmed that combining ipatasertib and TMZ treatment prolonged survival.
    CONCLUSIONS: Our findings highlighted AKT/Nrf2 pathways as a potential synthetic lethality target for IDH mutated cancers.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-3179
  12. Acta Neuropathol Commun. 2023 Jan 16. 11(1): 13
    CIC reduces xCT/SLC7A11 expression and glutamate release in glioma.
    Jong-Whi Park, Omer Kilic, Minh Deo, Kevin Jimenez-Cowell, Engin Demirdizen, Hyunggee Kim, Şevin Turcan.
      Capicua (CIC) is an important downstream molecule of RTK/RAS/MAPK pathway. The regulatory mechanism of CIC underlying tumorigenesis in oligodendroglioma, where CIC is frequently mutated, has yet to be fully elucidated. Using patient-derived glioma lines, RNA-sequencing and bioinformatic analysis of publicly available databases, we investigated how CIC loss- or gain-of-function regulates its downstream targets, cell proliferation and glutamate release. Our results indicate an increased frequency of CIC truncating mutations in oligodendroglioma during progression. In vitro, CIC modulation had a modest effect on cell proliferation in glioma lines, and no significant changes in the expression of ETV1, ETV4 and ETV5. Transcriptional repression of known CIC targets was observed in gliomas expressing non-phosphorylatable CIC variant on Ser173 which was unable to interact with 14-3-3. These data outline a mechanism by which the repressor function of CIC is inhibited by 14-3-3 in gliomas. Using transcriptional profiling, we found that genes related to glutamate release were upregulated because of CIC depletion. In addition, loss of CIC leads to increased extracellular glutamate. Consistent with this, CIC restoration in an oligodendroglioma line reduced the levels of extracellular glutamate, neuronal toxicity and xCT/SLC7A11 expression. Our findings may provide a molecular basis for the prevention of glioma-associated seizures.
    Keywords:  Capicua; Glutamate; Neuronal toxicity; Oligodendroglioma; xCT/SLC7A11
    DOI:  https://doi.org/10.1186/s40478-023-01507-y
  13. Cancer Discov. 2023 Jan 20. OF1
    Blood-Borne Myeloid Cell Loss of MHCII Drives Cytotoxic T-cell Dysfunction.
      MHCII expression on blood-borne myeloid cells is required for CD8+ T-cell function in glioma.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-010
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