bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2023–02–26
thirteen papers selected by
Oltea Sampetrean, Keio University



  1. Nat Commun. 2023 Feb 23. 14(1): 1028
      Diffuse midline glioma-H3K27M mutant (DMG) and glioblastoma (GBM) are the most lethal brain tumors that primarily occur in pediatric and adult patients, respectively. Both tumors exhibit significant heterogeneity, shaped by distinct genetic/epigenetic drivers, transcriptional programs including RNA splicing, and microenvironmental cues in glioma niches. However, the spatial organization of cellular states and niche-specific regulatory programs remain to be investigated. Here, we perform a spatial profiling of DMG and GBM combining short- and long-read spatial transcriptomics, and single-cell transcriptomic datasets. We identify clinically relevant transcriptional programs, RNA isoform diversity, and multi-cellular ecosystems across different glioma niches. We find that while the tumor core enriches for oligodendrocyte precursor-like cells, radial glial stem-like (RG-like) cells are enriched in the neuron-rich invasive niche in both DMG and GBM. Further, we identify niche-specific regulatory programs for RG-like cells, and functionally confirm that FAM20C mediates invasive growth of RG-like cells in a neuron-rich microenvironment in a human neural stem cell derived orthotopic DMG model. Together, our results provide a blueprint for understanding the spatial architecture and niche-specific vulnerabilities of DMG and GBM.
    DOI:  https://doi.org/10.1038/s41467-023-36707-6
  2. Neuro Oncol. 2023 Feb 23. pii: noad047. [Epub ahead of print]
       BACKGROUND: High-grade gliomas (HGG) are aggressive brain tumors associated with short median patient survival and limited response to therapies, driving the need to develop tools to improve patient outcomes. Patient-derived xenograft (PDX) models, such as mouse PDX, have emerged as potential Avatar platforms for personalized oncology approaches, but the difficulty for some human grafts to grow successfully and the long time required for mice to develop tumors preclude their use for HGG.
    METHODS: We used a rapid and efficient ex-ovo chicken embryo ChorioAllantoic Membrane (CAM) culture system to evaluate the efficacy of oncologic drug options for HGG patients.
    RESULTS: Implantation of fresh glioma tissue fragments from 59 of 60 patients, that include difficult to growth IDH-mutated samples, successfully established CAM tumor xenografts within 7 days, with a tumor take rate of 98.3%. These xenografts faithfully recapitulate the histological and molecular characteristics of the primary tumor, and the ability of individual fragments to form tumors was predictive of poor patient prognosis. Treatment of drug-sensitive or drug-resistant xenografts indicates that the CAM-glioma assay enables testing tumor sensitivity to temozolomide and carboplatin at doses consistent with those administered to patients. In a proof-of-concept study involving 14 HGG patients, we observed a correlation of 100% between the CAM xenograft response to temozolomide or carboplatin and the clinical response of patients.
    CONCLUSION: The CAM-glioma model is a fast and reliable assay that has the potential to serve as a complementary model to drug discovery and a real-time Avatar platform to predict the best treatment for HGG patients.
    Keywords:  Avatar model; Chick chorioallantoic membrane assay; glioblastoma; patient-derived xenograft model; personalized medicine
    DOI:  https://doi.org/10.1093/neuonc/noad047
  3. Cancer Discov. 2023 Feb 24. OF1
      Toosendanin (TSN) converts macrophages from immunosuppressive to immunostimulatory in glioblastoma.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-030
  4. JAMA. 2023 02 21. 329(7): 574-587
       Importance: Malignant primary brain tumors cause more than 15 000 deaths per year in the United States. The annual incidence of primary malignant brain tumors is approximately 7 per 100 000 individuals and increases with age. Five-year survival is approximately 36%.
    Observations: Approximately 49% of malignant brain tumors are glioblastomas, and 30% are diffusely infiltrating lower-grade gliomas. Other malignant brain tumors include primary central nervous system (CNS) lymphoma (7%) and malignant forms of ependymomas (3%) and meningiomas (2%). Symptoms of malignant brain tumors include headache (50%), seizures (20%-50%), neurocognitive impairment (30%-40%), and focal neurologic deficits (10%-40%). Magnetic resonance imaging before and after a gadolinium-based contrast agent is the preferred imaging modality for evaluating brain tumors. Diagnosis requires tumor biopsy with consideration of histopathological and molecular characteristics. Treatment varies by tumor type and often includes a combination of surgery, chemotherapy, and radiation. For patients with glioblastoma, the combination of temozolomide with radiotherapy improved survival when compared with radiotherapy alone (2-year survival, 27.2% vs 10.9%; 5-year survival, 9.8% vs 1.9%; hazard ratio [HR], 0.6 [95% CI, 0.5-0.7]; P < .001). In patients with anaplastic oligodendroglial tumors with 1p/19q codeletion, probable 20-year overall survival following radiotherapy without vs with the combination of procarbazine, lomustine, and vincristine was 13.6% vs 37.1% (80 patients; HR, 0.60 [95% CI, 0.35-1.03]; P = .06) in the EORTC 26951 trial and 14.9% vs 37% in the RTOG 9402 trial (125 patients; HR, 0.61 [95% CI, 0.40-0.94]; P = .02). Treatment of primary CNS lymphoma includes high-dose methotrexate-containing regimens, followed by consolidation therapy with myeloablative chemotherapy and autologous stem cell rescue, nonmyeloablative chemotherapy regimens, or whole brain radiation.
    Conclusions and Relevance: The incidence of primary malignant brain tumors is approximately 7 per 100 000 individuals, and approximately 49% of primary malignant brain tumors are glioblastomas. Most patients die from progressive disease. First-line therapy for glioblastoma is surgery followed by radiation and the alkylating chemotherapeutic agent temozolomide.
    DOI:  https://doi.org/10.1001/jama.2023.0023
  5. Cell Metab. 2023 Feb 16. pii: S1550-4131(23)00010-4. [Epub ahead of print]
      The efficacy of immunotherapy is limited by the paucity of T cells delivered and infiltrated into the tumors through aberrant tumor vasculature. Here, we report that phosphoglycerate dehydrogenase (PHGDH)-mediated endothelial cell (EC) metabolism fuels the formation of a hypoxic and immune-hostile vascular microenvironment, driving glioblastoma (GBM) resistance to chimeric antigen receptor (CAR)-T cell immunotherapy. Our metabolome and transcriptome analyses of human and mouse GBM tumors identify that PHGDH expression and serine metabolism are preferentially altered in tumor ECs. Tumor microenvironmental cues induce ATF4-mediated PHGDH expression in ECs, triggering a redox-dependent mechanism that regulates endothelial glycolysis and leads to EC overgrowth. Genetic PHGDH ablation in ECs prunes over-sprouting vasculature, abrogates intratumoral hypoxia, and improves T cell infiltration into the tumors. PHGDH inhibition activates anti-tumor T cell immunity and sensitizes GBM to CAR T therapy. Thus, reprogramming endothelial metabolism by targeting PHGDH may offer a unique opportunity to improve T cell-based immunotherapy.
    Keywords:  ATF4; CAR T immunotherapy; PHGDH; endothelial metabolism; glycolysis; vascular pruning
    DOI:  https://doi.org/10.1016/j.cmet.2023.01.010
  6. Clin Cancer Res. 2023 Feb 24. pii: CCR-23-0018. [Epub ahead of print]
      Isocitrate dehydrogenase 1 mutant (IDH1m) gliomas are recalcitrant tumors for which radiotherapy (RT) remains a standard treatment. A recent study identified ZMYND8 as a key mediator of radio-resistance for IDH1m gliomas, and pharmacological targeting of this pathway may heighten RT-induced tumor response, providing a prospect of improved clinical outcomes.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-0018
  7. Neuro Oncol. 2023 Feb 20. pii: noad035. [Epub ahead of print]
       BACKGROUND: Glioblastoma growth impacts on the structure and physiology of peritumoral neuronal networks, altering the activity of pyramidal neurons which drives further tumor progression. It is therefore of paramount importance to identify glioma-induced changes in pyramidal neurons, since they represent a key therapeutic target.
    METHODS: We longitudinal monitored visual evoked potentials after the orthotopic implant of murine glioma cells into the mouse occipital cortex. With laser microdissection we analysed layer II-III pyramidal neurons molecular profile and with Local Field Potentials (LFP) recordings we evaluated the propensity to seizures in glioma-bearing animals with respect to control mice.
    RESULTS: We determine the time course of neuronal dysfunction of glioma-bearing mice and we identify a symptomatic stage, based on the decay of visual response. At that time point, we microdissect layer II-III pyramidal neurons and evaluate the expression of a panel of genes involved in synaptic transmission and neuronal excitability. Compared to the control group, peritumoral neurons show a decrease in the expression of the SNARE complex gene SNAP-25 and the alpha1 subunit of the GABA-A receptor. No significant changes are detected in glutamatergic (i.e., AMPA or NMDA receptor subunit) markers. Further reduction of GABA-A signalling by delivery of a benzodiazepine inverse agonist, DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate) precipitates seizures in two mouse models of tumor-bearing mice.
    CONCLUSIONS: These studies reveal novel molecular changes that occur in the principal cells of the tumor-adjacent zone. These modifications may be therapeutically targeted to ameliorate patients' quality of life.
    Keywords:  glioma; laser capture microdissection; mouse model; seizure; visual cortex
    DOI:  https://doi.org/10.1093/neuonc/noad035
  8. Nat Commun. 2023 Feb 20. 14(1): 941
      The major challenges of immunotherapy for glioblastoma are that drugs cannot target tumor sites accurately and properly activate complex immune responses. Herein, we design and prepare a kind of chemotactic nanomotor loaded with brain endothelial cell targeting agent angiopep-2 and anti-tumor drug (Lonidamine modified with mitochondrial targeting agent triphenylphosphine, TLND). Reactive oxygen species and inducible nitric oxide synthase (ROS/iNOS), which are specifically highly expressed in glioblastoma microenvironment, are used as chemoattractants to induce the chemotactic behavior of the nanomotors. We propose a precise targeting strategy of brain endothelial cells-tumor cells-mitochondria. Results verified that the released NO and TLND can regulate the immune circulation through multiple steps to enhance the effect of immunotherapy, including triggering the immunogenic cell death of tumor, inducing dendritic cells to mature, promoting cytotoxic T cells infiltration, and regulating tumor microenvironment. Moreover, this treatment strategy can form an effective immune memory effect to prevent tumor metastasis and recurrence.
    DOI:  https://doi.org/10.1038/s41467-022-35709-0
  9. Neuro Oncol. 2023 Feb 22. pii: noad042. [Epub ahead of print]
       BACKGROUND: While recent sequencing studies have revealed that 10% of childhood gliomas are caused by rare germline mutations, the role of common variants is undetermined and no genome-wide significant risk loci for pediatric CNS tumors have been identified to date.
    METHODS: Meta-analysis of three population-based genome-wide association studies (GWASs) comprising 4,069 children with glioma and 8,778 controls of multiple genetic ancestries. Replication was performed in a separate case-control cohort. Quantitative trait loci analyses and a transcriptome-wide association study were conducted to assess possible links with brain tissue expression across 18,628 genes.
    RESULTS: Common variants in CDKN2B-AS1 at 9p21.3 were significantly associated with astrocytoma, the most common subtype of glioma in children (rs573687, p-value 6.974e-10, OR 1.273, CI95 1.179-1.374). The association was driven by low-grade astrocytoma (p-value 3.815e-9) and exhibited unidirectional effects across all six genetic ancestries. For glioma overall, the association approached genome-wide significance (rs3731239, p-value 5.411e-8), while no significant association was observed for high-grade tumors. Predicted decreased brain tissue expression of CDKN2B was significantly associated with astrocytoma (p-value 8.090e-8).
    CONCLUSION: In this population-based GWAS meta-analysis, we identify and replicate 9p21.3 (CDKN2B-AS1) as a risk locus for childhood astrocytoma, thereby establishing the first genome-wide significant evidence of common variant predisposition in pediatric neuro-oncology. We furthermore provide a functional basis for the association by showing a possible link to decreased brain tissue CDKN2B expression and substantiate that genetic susceptibility differs between low- and high-grade astrocytoma.
    Keywords:  GWAS; childhood brain tumors; genetic susceptibility; glioma; pediatric neuro-oncology
    DOI:  https://doi.org/10.1093/neuonc/noad042
  10. Neuro Oncol. 2023 Feb 21. pii: noad045. [Epub ahead of print]
       PURPOSE: Cognitive functioning is increasingly assessed as a secondary outcome in neuro-oncological trials. However, which cognitive domains or tests to assess, remains debatable. In this meta-analysis, we aimed to elucidate the longer-term test-specific cognitive outcomes in adult glioma patients.
    METHODS: A systematic search yielded 7098 articles for screening. To investigate cognitive changes in glioma patients and differences between patients and controls ≥one-year follow-up, random-effects meta-analyses were conducted per cognitive test, separately for studies with a longitudinal and cross-sectional design. A meta-regression analysis with a moderator for interval testing (additional cognitive testing between baseline and one-year post-treatment) was performed to investigate the impact of practice in longitudinal designs.
    RESULTS: Eighty-three studies were reviewed, of which 37 were analyzed in the meta-analysis, involving 4078 patients. In longitudinal designs, semantic fluency was the most sensitive test to detect cognitive decline over time. Cognitive performance on MMSE, digit span forward, phonemic and semantic fluency declined over time in patients who had no interval testing. In cross-sectional studies, patients performed worse than controls on the MMSE, digit span backward, semantic fluency, Stroop speed interference task, trail making test B and finger tapping.
    CONCLUSION: Cognitive performance of glioma patients one year after treatment is significantly lower compared to the norm, with specific tests potentially being more sensitive. Cognitive decline over time occurs as well, but can easily be overlooked in longitudinal designs due to practice effects (as a result of interval testing). It is warranted to sufficiently correct for practice effects in future longitudinal trials.
    Keywords:  Adult; Cognition; Cognitive evaluation; Glioma; Meta-analysis
    DOI:  https://doi.org/10.1093/neuonc/noad045
  11. Neuro Oncol. 2023 Feb 20. pii: noad031. [Epub ahead of print]
       BACKGROUND: Therapeutic options are limited in pediatric CNS malignancies. CheckMate 908 (NCT03130959) is an open-label, sequential-arm, phase 1b/2 study investigating nivolumab (NIVO) and NIVO+ipilimumab (IPI) in pediatric patients with high-grade CNS malignancies.
    METHODS: Patients (N=166) in 5 cohorts received NIVO 3 mg/kg every 2 weeks (Q2W) or NIVO 3 mg/kg+IPI 1 mg/kg every 3 weeks (4 doses) followed by NIVO 3 mg/kg Q2W. Primary endpoints included overall survival (OS; newly diagnosed diffuse intrinsic pontine glioma [DIPG]) and progression-free survival (PFS; other recurrent/progressive or relapsed/resistant CNS cohorts). Secondary endpoints included other efficacy metrics and safety. Exploratory endpoints included pharmacokinetics and biomarker analyses.
    RESULTS: As of January 13, 2021, median OS (80% CI) was 11.7 (10.3-16.5) and 10.8 (9.1-15.8) months with NIVO and NIVO+IPI, respectively, in newly diagnosed DIPG. Median PFS (80% CI) with NIVO and NIVO+IPI was 1.7 (1.4-2.7) and 1.3 (1.2-1.5) months, respectively, in recurrent/progressive high-grade glioma; 1.4 (1.2-1.4) and 2.8 (1.5-4.5) months in relapsed/resistant medulloblastoma; and 1.4 (1.4-2.6) and 4.6 (1.4-5.4) months in relapsed/resistant ependymoma. In patients with other recurrent/progressive CNS tumors, median PFS (95% CI) was 1.2 (1.1-1.3) and 1.6 (1.3-3.5) months, respectively. Grade 3/4 treatment-related adverse-event rates were 14.1% (NIVO) and 27.2% (NIVO+IPI). NIVO and IPI first-dose trough concentrations were lower in youngest and lowest-weight patients. Baseline tumor programmed death ligand 1 expression was not associated with survival.
    CONCLUSIONS: NIVO±IPI did not demonstrate clinical benefit relative to historical data. The overall safety profiles were manageable with no new safety signals.
    Keywords:  DIPG; HGG; checkpoint inhibitors; ependymoma; medulloblastoma
    DOI:  https://doi.org/10.1093/neuonc/noad031
  12. Nat Med. 2023 Feb 23.
      Vorasidenib and ivosidenib inhibit mutant forms of isocitrate dehydrogenase (mIDH) and have shown preliminary clinical activity against mIDH glioma. We evaluated both agents in a perioperative phase 1 trial to explore the mechanism of action in recurrent low-grade glioma (IGG) and select a molecule for phase 3 testing. Primary end-point was concentration of D-2-hydroxyglutarate (2-HG), the metabolic product of mIDH enzymes, measured in tumor tissue from 49 patients with mIDH1-R132H nonenhancing gliomas following randomized treatment with vorasidenib (50 mg or 10 mg once daily, q.d.), ivosidenib (500 mg q.d. or 250 mg twice daily) or no treatment before surgery. Tumor 2-HG concentrations were reduced by 92.6% (95% credible interval (CrI), 76.1-97.6) and 91.1% (95% CrI, 72.0-97.0) in patients treated with vorasidenib 50 mg q.d. and ivosidenib 500 mg q.d., respectively. Both agents were well tolerated and follow-up is ongoing. In exploratory analyses, 2-HG reduction was associated with increased DNA 5-hydroxymethylcytosine, reversal of 'proneural' and 'stemness' gene expression signatures, decreased tumor cell proliferation and immune cell activation. Vorasidenib, which showed brain penetrance and more consistent 2-HG suppression than ivosidenib, was advanced to phase 3 testing in patients with mIDH LGGs. Funded by Agios Pharmaceuticals, Inc. and Servier Pharmaceuticals LLC; ClinicalTrials.gov number NCT03343197.
    DOI:  https://doi.org/10.1038/s41591-022-02141-2