bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2022–05–29
eightteen papers selected by
Oltea Sampetrean, Keio University
  1. Dysfunctional dendritic cells limit antigen-specific T cell response in glioma.
  2. Radiotherapy-drug combinations in the treatment of glioblastoma: a brief review.
  3. Mechanism and therapeutic potential of tumor-immune symbiosis in glioblastoma.
  4. Orthotopic Transplantation of Human Paediatric High-Grade Glioma in Zebrafish Larvae.
  5. Single-cell RNA sequencing reveals evolution of immune landscape during glioblastoma progression.
  6. Integrin-αvβ3 as a Therapeutic Target in Glioblastoma: Back to the Future?
  7. Efficacy of laser interstitial thermal therapy (LITT) for newly diagnosed and recurrent IDH wild-type glioblastoma.
  8. Notch signaling in malignant gliomas: supporting tumor growth and the vascular environment.
  9. High DKK3 expression related to immunosuppression was associated with poor prognosis in glioblastoma: machine learning approach.
  10. Non-metabolic functions of phosphofructokinase-1 orchestrate tumor cellular invasion and genome maintenance under bevacizumab therapy.
  11. Combination of DNA Vaccine and Immune Checkpoint Blockades Improves the Immune Response in an Orthotopic Unresectable Glioblastoma Model.
  12. Systemic Delivery of an Adjuvant CXCR4-CXCL12 Signaling Inhibitor Encapsulated in Synthetic Protein Nanoparticles for Glioma Immunotherapy.
  13. Diagnostic and Prognostic Value of pH- and Oxygen-Sensitive Magnetic Resonance Imaging in Glioma: A Retrospective Study.
  14. Inhibition of D-2HG leads to upregulation of a proinflammatory gene signature in a novel HLA-A2/HLA-DR1 transgenic mouse model of IDH1R132H-expressing glioma.
  15. Multi-institutional study of the frequency, genomic landscape and outcome of IDH-mutant glioma in paediatrics.
  16. Therapeutic targeting of prenatal pontine ID1 signaling in diffuse midline glioma.
  17. A randomized feasibility study evaluating temozolomide circadian medicine in patients with glioma.
  18. Mapping the tumor-infiltrating immune cells during glioblastoma progression.
  1. Neuro Oncol. 2022 May 24. pii: noac138. [Epub ahead of print]
    Dysfunctional dendritic cells limit antigen-specific T cell response in glioma.
    Mirco Friedrich, Markus Hahn, Julius Michel, Roman Sankowski, Michael Kilian, Niklas Kehl, Manina Günter, Theresa Bunse, Stefan Pusch, Andreas von Deimling, Wolfgang Wick, Stella E Autenrieth, Marco Prinz, Michael Platten, Lukas Bunse.
       BACKGROUND: Dendritic cells (DC), the most potent professional antigen presenting cells capable of effective cross-presentation, have been demonstrated to license T helper cells to induce anti-tumor immunity in solid tumors. Specific DC subtypes are recruited to the injured brain by microglial chemokines, locally adapting to distinct transcriptional profiles. In isocitrate dehydrogenase type 1 (IDH) mutant gliomas, monocyte-derived macrophages have recently been shown to display an attenuated intratumoral antigen presentation capacity as consequence of the local accumulation of the oncometabolite R-2-hydroxyglutarate. The functionality and the contribution of DC to the IDH-mutant tumor microenvironment (TME) remains unclear.
    METHODS: Frequencies and intratumoral phenotypes of human DC in IDH-wildtype and -mutant high-grade gliomas are comparatively assessed by transcriptomic and proteomic profiling. DC functionality is investigated in experimental murine glioblastomas expressing the model antigen ovalbumin. Single-cell sequencing-based pseudotime analyses and spectral flow cytometric analyses are used to profile DC states longitudinally.
    RESULTS: DC are present in primary and recurrent high-grade gliomas and interact with other immune cell types within the TME. In murine glioblastomas, we find an IDH-status-associated major histocompatibility class I-restricted cross-presentation of tumor antigens by DC specifically in the tumor but not in meninges or secondary lymphoid organs of tumor-bearing animals. In single-cell sequencing-based pseudotime and longitudinal spectral flow cytometric analyses, we demonstrate an IDH-status-dependent differential, exclusively microenvironmental education of DC.
    CONCLUSION: Glioma-associated DCs are relevantly abundant in human IDH wildtype and mutant tumors. Glioma IDH mutations result in specifically educated, dysfunctional DCs via paracrine reprogramming of infiltrating monocytes, providing the basis for combinatorial immunotherapy concepts against IDH mutant gliomas.
    Keywords:  IDH mutation; R-2-HG; cDC1; cDC2; dendritic cell; glioblastoma; glioma microenvironment
    DOI:  https://doi.org/10.1093/neuonc/noac138
  2. CNS Oncol. 2022 Jun 01. 11(2): CNS86
    Radiotherapy-drug combinations in the treatment of glioblastoma: a brief review.
    Patrick G McAleavey, Gerard M Walls, Anthony J Chalmers.
      Glioblastoma (GBM) accounts for over 50% of gliomas and carries the worst prognosis of all solid tumors. Owing to the limited local control afforded by surgery alone, efficacious adjuvant treatments such as radiotherapy (RT) and chemotherapy are fundamental in achieving durable disease control. The best clinical outcomes are achieved with tri-modality treatment consisting of surgery, RT and systemic therapy. While RT-chemotherapy combination regimens are well established in oncology, this approach was largely unsuccessful in GBM until the introduction of temozolomide. The success of this combination has stimulated the search for other candidate drugs for concomitant use with RT in GBM. This review seeks to collate the current evidence for these agents and synthesize possible future directions for the field.
    Keywords:  chemotherapy; glioblastoma; radiosensitizers; radiotherapy; trial design
    DOI:  https://doi.org/10.2217/cns-2021-0015
  3. Trends Cancer. 2022 May 24. pii: S2405-8033(22)00097-8. [Epub ahead of print]
    Mechanism and therapeutic potential of tumor-immune symbiosis in glioblastoma.
    Lizhi Pang, Fatima Khan, Amy B Heimberger, Peiwen Chen.
      Glioblastoma (GBM) is the most aggressive and lethal form of brain tumor in human adults. Myeloid-lineage cells, including macrophages, microglia, myeloid-derived suppressor cells (MDSCs), and neutrophils, are the most frequent types of cell in the GBM tumor microenvironment (TME) that contribute to tumor progression. Emerging experimental evidence indicates that symbiotic interactions between cancer cells and myeloid cells are critical for tumor growth and immunotherapy resistance in GBM. In this review, we discuss the molecular mechanisms whereby cancer cells shape a myeloid cell-mediated immunosuppressive TME and, reciprocally, how such myeloid cells affect tumor progression and immunotherapy efficiency in GBM. Moreover, we highlight tumor-T cell symbiosis and summarize immunotherapeutic strategies intercepting this co-dependency in GBM.
    Keywords:  MDSCs; glioblastoma; immunotherapy; macrophages; microglia; symbiosis
    DOI:  https://doi.org/10.1016/j.trecan.2022.04.010
  4. Brain Sci. 2022 May 10. pii: 625. [Epub ahead of print]12(5):
    Orthotopic Transplantation of Human Paediatric High-Grade Glioma in Zebrafish Larvae.
    Susanna Larsson, Petronella Kettunen, Helena Carén.
      Brain tumours are the most common cause of death among children with solid tumours, and high-grade gliomas (HGG) are among the most devastating forms with very poor outcomes. In the search for more effective treatments for paediatric HGG, there is a need for better experimental models. To date, there are no xenograft zebrafish models developed for human paediatric HGG; existing models rely on adult cells. The use of paediatric models is of great importance since it is well known that the genetic and epigenetic mechanisms behind adult and paediatric disease differ greatly. In this study, we present a clinically relevant in vivo model based on paediatric primary glioma stem cell (GSC) cultures, which after orthotopic injection into the zebrafish larvae, can be monitored using confocal imaging over time. We show that cells invade the brain tissue and can be followed up to 8 days post-injection while they establish in the fore/mid brain. This model offers an in vivo system where tumour invasion can be monitored and drug treatments quickly be evaluated. The possibility to monitor patient-specific cells has the potential to contribute to a better understanding of cellular behaviour and personalised treatments in the future.
    Keywords:  cancer stem cells; epigenetics; experimental model; glioma stem cells; in vivo model; paediatric glioblastoma; paediatric high-grade glioma; zebrafish larvae
    DOI:  https://doi.org/10.3390/brainsci12050625
  5. Nat Immunol. 2022 May 27.
    Single-cell RNA sequencing reveals evolution of immune landscape during glioblastoma progression.
    Alan T Yeo, Shruti Rawal, Bethany Delcuze, Anthos Christofides, Agata Atayde, Laura Strauss, Leonora Balaj, Vaughn A Rogers, Erik J Uhlmann, Hemant Varma, Bob S Carter, Vassiliki A Boussiotis, Al Charest.
      Glioblastoma (GBM) is an incurable primary malignant brain cancer hallmarked with a substantial protumorigenic immune component. Knowledge of the GBM immune microenvironment during tumor evolution and standard of care treatments is limited. Using single-cell transcriptomics and flow cytometry, we unveiled large-scale comprehensive longitudinal changes in immune cell composition throughout tumor progression in an epidermal growth factor receptor-driven genetic mouse GBM model. We identified subsets of proinflammatory microglia in developing GBMs and anti-inflammatory macrophages and protumorigenic myeloid-derived suppressors cells in end-stage tumors, an evolution that parallels breakdown of the blood-brain barrier and extensive growth of epidermal growth factor receptor+ GBM cells. A similar relationship was found between microglia and macrophages in patient biopsies of low-grade glioma and GBM. Temozolomide decreased the accumulation of myeloid-derived suppressor cells, whereas concomitant temozolomide irradiation increased intratumoral GranzymeB+ CD8+T cells but also increased CD4+ regulatory T cells. These results provide a comprehensive and unbiased immune cellular landscape and its evolutionary changes during GBM progression.
    DOI:  https://doi.org/10.1038/s41590-022-01215-0
  6. Pharmaceutics. 2022 May 13. pii: 1053. [Epub ahead of print]14(5):
    Integrin-αvβ3 as a Therapeutic Target in Glioblastoma: Back to the Future?
    William Echavidre, Vincent Picco, Marc Faraggi, Christopher Montemagno.
      Glioblastoma (GBM), the most common primary malignant brain tumor, is associated with a dismal prognosis. Standard therapies including maximal surgical resection, radiotherapy, and temozolomide chemotherapy remain poorly efficient. Improving GBM treatment modalities is, therefore, a paramount challenge for researchers and clinicians. GBMs exhibit the hallmark feature of aggressive invasion into the surrounding tissue. Among cell surface receptors involved in this process, members of the integrin family are known to be key actors of GBM invasion. Upregulation of integrins was reported in both tumor and stromal cells, making them a suitable target for innovative therapies targeting integrins in GBM patients, as their impairment disrupts tumor cell proliferation and invasive capacities. Among them, integrin-αvβ3 expression correlates with high-grade GBM. Driven by a plethora of preclinical biological studies, antagonists of αvβ3 rapidly became attractive therapeutic candidates to impair GBM tumorigenesis. In this perspective, the advent of nuclear medicine is currently one of the greatest components of the theranostic concept in both preclinical and clinical research fields. In this review, we provided an overview of αvβ3 expression in GBM to emphasize the therapeutic agents developed. Advanced current and future developments in the theranostic field targeting αvβ3 are finally discussed.
    Keywords:  cilengitide; glioblastoma; integrins; nuclear medicine; theranostics
    DOI:  https://doi.org/10.3390/pharmaceutics14051053
  7. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac040
    Efficacy of laser interstitial thermal therapy (LITT) for newly diagnosed and recurrent IDH wild-type glioblastoma.
    John F de Groot, Albert H Kim, Sujit Prabhu, Ganesh Rao, Adrian W Laxton, Peter E Fecci, Barbara J O'Brien, Andrew Sloan, Veronica Chiang, Stephen B Tatter, Alireza M Mohammadi, Dimitris G Placantonakis, Roy E Strowd, Clark Chen, Constantinos Hadjipanayis, Mustafa Khasraw, David Sun, David Piccioni, Kaylyn D Sinicrope, Jian L Campian, Sylvia C Kurz, Brian Williams, Kris Smith, Zulma Tovar-Spinoza, Eric C Leuthardt.
       Background: Treatment options for unresectable new and recurrent glioblastoma remain limited. Laser ablation has demonstrated safety as a surgical approach to treating primary brain tumors. The LAANTERN prospective multicenter registry (NCT02392078) data were analyzed to determine clinical outcomes for patients with new and recurrent IDH wild-type glioblastoma.
    Methods: Demographics, intraprocedural data, adverse events, KPS, health economics, and survival data were prospectively collected and then analyzed on IDH wild-type newly diagnosed and recurrent glioblastoma patients who were treated with laser ablation at 14 US centers between January 2016 and May 2019. Data were monitored for accuracy. Statistical analysis included individual variable summaries, multivariable differences in survival, and median survival numbers.
    Results: A total of 29 new and 60 recurrent IDH wild-type WHO grade 4 glioblastoma patients were treated. Positive MGMT promoter methylation status was present in 5/29 of new and 23/60 of recurrent patients. Median physician-estimated extent of ablation was 91%-99%. Median overall survival (OS) was 9.73 months (95% confidence interval: 5.16, 15.91) for newly diagnosed patients and median post-procedure survival was 8.97 months (6.94, 12.36) for recurrent patients. Median OS for newly diagnosed patients receiving post-LITT chemo/radiation was 16.14 months (6.11, not reached). Factors associated with improved survival were MGMT promoter methylation, adjuvant chemotherapy within 12 weeks, and tumor volume <3 cc.
    Conclusions: Laser ablation is a viable option for patients with new and recurrent glioblastoma. Median OS for IDH wild-type newly diagnosed glioblastoma is comparable to outcomes observed in other tumor resection studies when those patients undergo radiation and chemotherapy following LITT.
    Keywords:  IDH wild-type WHO grade 4 glioblastoma; high-grade glioma; laser interstitial thermal therapy (LITT); primary brain tumor; stereotactic laser ablation (SLA)
    DOI:  https://doi.org/10.1093/noajnl/vdac040
  8. Cancer Metastasis Rev. 2022 May 27.
    Notch signaling in malignant gliomas: supporting tumor growth and the vascular environment.
    Franciele C Kipper, Mark W Kieran, Ajith Thomas, Dipak Panigrahy.
      Glioblastoma is the most malignant form of glioma, which is the most commonly occurring tumor of the central nervous system. Notch signaling in glioblastoma is considered to be a marker of an undifferentiated tumor cell state, associated with tumor stem cells. Notch is also known for facilitating tumor dormancy escape, recurrence and progression after treatment. Studies in vitro suggest that reducing, removing or blocking the expression of this gene triggers tumor cell differentiation, which shifts the phenotype away from stemness status and consequently facilitates treatment. In contrast, in the vasculature, Notch appears to also function as an important receptor that defines mature non-leaking vessels, and increasing its expression promotes tumor normalization in models of cancer in vivo. Failures in clinical trials with Notch inhibitors are potentially related to their opposing effects on the tumor versus the tumor vasculature, which points to the need for a greater understanding of this signaling pathway.
    Keywords:  Angiogenesis; Cancer stem cell; Glioblastoma; Notch pathway
    DOI:  https://doi.org/10.1007/s10555-022-10041-7
  9. Cancer Immunol Immunother. 2022 May 23.
    High DKK3 expression related to immunosuppression was associated with poor prognosis in glioblastoma: machine learning approach.
    Myung-Hoon Han, Kyueng-Whan Min, Yung-Kyun Noh, Jae Min Kim, Jin Hwan Cheong, Je Il Ryu, Yu Deok Won, Seong-Ho Koh, Jae Kyung Myung, Ji Young Park, Mi Jung Kwon.
       BACKGROUND: Glioblastoma multiforme (GBM) is an aggressive malignant primary brain tumor. Wnt/β-catenin is known to be related to GBM stemness. Cancer stem cells induce immunosuppressive and treatment resistance in GBM. We hypothesized that Wnt/β-catenin-related genes with immunosuppression could be related to the prognosis in patients with GBM.
    METHODS: We obtained the clinicopathological data of 525 patients with GBM from the brain cancer gene database. The fraction of tumor-infiltrating immune cells was evaluated using in silico flow cytometry. Among gene sets of Wnt/β-catenin pathway, Dickkopf-3 (DKK3) gene related to the immunosuppressive response was found using machine learning. We performed gene set enrichment analysis (GSEA), network-based analysis, survival analysis and in vitro drug screening assays based on Dickkopf-3 (DKK3) expression.
    RESULTS: In analyses of 31 genes related to Wnt/β-catenin signaling, high DKK3 expression was negatively correlated with increased antitumoral immunity, especially CD8 + and CD4 + T cells, in patients with GBM. High DKK3 expression was correlated with poor survival and disease progression in patients with GBM. In pathway-based network analysis, DKK3 was directly linked to the THY1 gene, a tumor suppressor gene. Through in vitro drug screening, we identified navitoclax as an agent with potent activity against GBM cell lines with high DKK3 expression.
    CONCLUSIONS: These results suggest that high DKK3 expression could be a therapeutic target in GBM. The results of the present study could contribute to the design of future experimental research and drug development programs for GBM.
    Keywords:  Dickkopf-3; Gene; Glioblastoma multiforme; Survival; Wnt/β-catenin signaling
    DOI:  https://doi.org/10.1007/s00262-022-03222-4
  10. Neuro Oncol. 2022 May 24. pii: noac135. [Epub ahead of print]
    Non-metabolic functions of phosphofructokinase-1 orchestrate tumor cellular invasion and genome maintenance under bevacizumab therapy.
    Yi Chieh Lim, Kamilla E Jensen, Diana Aguilar-Morante, Lina Vardouli, Kristoffer Vitting-Seerup, Ryan C Gimple, Qiulian Wu, Henriette Pedersen, Kirstine J Elbaek, Irina Gromova, Robert Ihnatko, Bjarne W Kristensen, Jeanette K Petersen, Jane Skjoth-Rasmussen, William Flavahan, Jeremy N Rich, Petra Hamerlik.
       BACKGROUND: Glioblastoma (GBM) is a highly lethal malignancy for which neoangiogenesis serves as a defining hallmark. The anti-VEGF antibody, bevacizumab, has been approved for the treatment of recurrent GBM, but resistance is universal.
    METHODS: We analyzed expression data of GBM patients treated with bevacizumab to discover potential resistance mechanisms. Patient-derived xenografts (PDXs) and cultures were interrogated for effects of phosphofructokinase-1, muscle isoform (PFKM) loss on tumor cell motility, migration, and invasion through genetic and pharmacologic targeting.
    RESULTS: We identified PFKM as a driver of bevacizumab resistance. PFKM functions dichotomize based on subcellular location: Cytosolic PFKM interacted with KIF11, a tubular motor protein, to promote tumor invasion, whereas nuclear PFKM safeguarded genomic stability of tumor cells through interaction with NBS1. Leveraging transcriptional profiles, bupivacaine phenocopied genetic targeting of PFKM and enhanced efficacy of bevacizumab in preclinical GBM models in vivo.
    CONCLUSION: PFKM drives novel molecular pathways in GBM, offering a translational path to a novel therapeutic paradigm.
    Keywords:  Bevacizumab; DNA damage; Invasion; PFKM; repair
    DOI:  https://doi.org/10.1093/neuonc/noac135
  11. Pharmaceutics. 2022 May 10. pii: 1025. [Epub ahead of print]14(5):
    Combination of DNA Vaccine and Immune Checkpoint Blockades Improves the Immune Response in an Orthotopic Unresectable Glioblastoma Model.
    Mathilde Bausart, Kevin Vanvarenberg, Bernard Ucakar, Alessandra Lopes, Gaëlle Vandermeulen, Alessio Malfanti, Véronique Préat.
      Combination immunotherapy has emerged as a promising strategy to increase the immune response in glioblastoma (GBM) and overcome the complex immunosuppression occurring in its microenvironment. In this study, we hypothesized that combining DNA vaccines-to stimulate a specific immune response-and dual immune checkpoint blockade (ICB)-to decrease the immunosuppression exerted on T cells-will improve the immune response and the survival in an orthotopic unresectable GL261 model. We first highlighted the influence of the insertion position of a GBM epitope sequence in a plasmid DNA vaccine encoding a vesicular stomatitis virus glycoprotein (VSV-G) (here referred to as pTOP) in the generation of a specific and significant IFN-γ response against the GBM antigen TRP2 by inserting a CD8 epitope sequence in specific permissive sites. Then, we combined the pTOP vaccine with anti-PD-1 and anti-CTLA-4 ICBs. Immune cell analysis revealed an increase in effector T cell to Treg ratios in the spleens and an increase in infiltrated IFN-γ-secreting CD8 T cell frequency in the brains following combination therapy. Even if the survival was not significantly different between dual ICB and combination therapy, we offer a new immunotherapeutic perspective by improving the immune landscape in an orthotopic unresectable GBM model.
    Keywords:  combination immunotherapy; glioblastoma; immune checkpoint blockade; plasmid DNA vaccine
    DOI:  https://doi.org/10.3390/pharmaceutics14051025
  12. ACS Nano. 2022 May 26.
    Systemic Delivery of an Adjuvant CXCR4-CXCL12 Signaling Inhibitor Encapsulated in Synthetic Protein Nanoparticles for Glioma Immunotherapy.
    Mahmoud S Alghamri, Kaushik Banerjee, Anzar A Mujeeb, Ava Mauser, Ayman Taher, Rohit Thalla, Brandon L McClellan, Maria L Varela, Svetlana M Stamatovic, Gabriela Martinez-Revollar, Anuska V Andjelkovic, Jason V Gregory, Padma Kadiyala, Alexandra Calinescu, Jennifer A Jiménez, April A Apfelbaum, Elizabeth R Lawlor, Stephen Carney, Andrea Comba, Syed Mohd Faisal, Marcus Barissi, Marta B Edwards, Henry Appelman, Yilun Sun, Jingyao Gan, Rose Ackermann, Anna Schwendeman, Marianela Candolfi, Michael R Olin, Joerg Lahann, Pedro R Lowenstein, Maria G Castro.
      Glioblastoma (GBM) is an aggressive primary brain cancer, with a 5 year survival of ∼5%. Challenges that hamper GBM therapeutic efficacy include (i) tumor heterogeneity, (ii) treatment resistance, (iii) immunosuppressive tumor microenvironment (TME), and (iv) the blood-brain barrier (BBB). The C-X-C motif chemokine ligand-12/C-X-C motif chemokine receptor-4 (CXCL12/CXCR4) signaling pathway is activated in GBM and is associated with tumor progression. Although the CXCR4 antagonist (AMD3100) has been proposed as an attractive anti-GBM therapeutic target, it has poor pharmacokinetic properties, and unfavorable bioavailability has hampered its clinical implementation. Thus, we developed synthetic protein nanoparticles (SPNPs) coated with the transcytotic peptide iRGD (AMD3100-SPNPs) to target the CXCL2/CXCR4 pathway in GBM via systemic delivery. We showed that AMD3100-SPNPs block CXCL12/CXCR4 signaling in three mouse and human GBM cell cultures in vitro and in a GBM mouse model in vivo. This results in (i) inhibition of GBM proliferation, (ii) reduced infiltration of CXCR4+ monocytic myeloid-derived suppressor cells (M-MDSCs) into the TME, (iii) restoration of BBB integrity, and (iv) induction of immunogenic cell death (ICD), sensitizing the tumor to radiotherapy and leading to anti-GBM immunity. Additionally, we showed that combining AMD3100-SPNPs with radiation led to long-term survival, with ∼60% of GBM tumor-bearing mice remaining tumor free after rechallenging with a second GBM in the contralateral hemisphere. This was due to a sustained anti-GBM immunological memory response that prevented tumor recurrence without additional treatment. In view of the potent ICD induction and reprogrammed tumor microenvironment, this SPNP-mediated strategy has a significant clinical translation applicability.
    Keywords:  CXCL12/CXCR4; glioma; immunogenic cell death; immunotherapy; nanoparticles; synthetic protein; systemic delivery; tumor microenvironment
    DOI:  https://doi.org/10.1021/acsnano.1c07492
  13. Cancers (Basel). 2022 May 20. pii: 2520. [Epub ahead of print]14(10):
    Diagnostic and Prognostic Value of pH- and Oxygen-Sensitive Magnetic Resonance Imaging in Glioma: A Retrospective Study.
    Jingwen Yao, Akifumi Hagiwara, Talia C Oughourlian, Chencai Wang, Catalina Raymond, Whitney B Pope, Noriko Salamon, Albert Lai, Matthew Ji, Phioanh L Nghiemphu, Linda M Liau, Timothy F Cloughesy, Benjamin M Ellingson.
      Characterization of hypoxia and tissue acidosis could advance the understanding of glioma biology and improve patient management. In this study, we evaluated the ability of a pH- and oxygen-sensitive magnetic resonance imaging (MRI) technique to differentiate glioma genotypes, including isocitrate dehydrogenase (IDH) mutation, 1p/19q co-deletion, and epidermal growth factor receptor (EGFR) amplification, and investigated its prognostic value. A total of 159 adult glioma patients were scanned with pH- and oxygen-sensitive MRI at 3T. We quantified the pH-sensitive measure of magnetization transfer ratio asymmetry (MTRasym) and oxygen-sensitive measure of R2' within the tumor region-of-interest. IDH mutant gliomas showed significantly lower MTRasym × R2' (p &lt; 0.001), which differentiated IDH mutation status with sensitivity and specificity of 90.0% and 71.9%. Within IDH mutants, 1p/19q codeletion was associated with lower tumor acidity (p &lt; 0.0001, sensitivity 76.9%, specificity 91.3%), while IDH wild-type, EGFR-amplified gliomas were more hypoxic (R2' p = 0.024, sensitivity 66.7%, specificity 76.9%). Both R2' and MTRasym × R2' were significantly associated with patient overall survival (R2': p = 0.045; MTRasym × R2': p = 0.002) and progression-free survival (R2': p = 0.010; MTRasym × R2': p &lt; 0.0001), independent of patient age, treatment status, and IDH status. The pH- and oxygen-sensitive MRI is a clinically feasible and potentially valuable imaging technique for distinguishing glioma subtypes and providing additional prognostic value to clinical practice.
    Keywords:  genotype; glioma; multiparametric MRI; survival analysis; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers14102520
  14. J Immunother Cancer. 2022 May;pii: e004644. [Epub ahead of print]10(5):
    Inhibition of D-2HG leads to upregulation of a proinflammatory gene signature in a novel HLA-A2/HLA-DR1 transgenic mouse model of IDH1R132H-expressing glioma.
    Pavlina Chuntova, Akane Yamamichi, Tiffany Chen, Rohini Narayanaswamy, Sebastien Ronseaux, Christine Hudson, Adriana E Tron, Marc L Hyer, Megan Montoya, Abigail L Mende, Takahide Nejo, Kira M Downey, David Diebold, Min Lu, Brandon Nicolay, Hideho Okada.
       BACKGROUND: Long-term prognosis of WHO grade II, isocitrate dehydrogenase (IDH)-mutated low-grade glioma (LGG) is poor due to high risks of recurrence and malignant transformation into high-grade glioma. Immunotherapy strategies are attractive given the relatively intact immune system of patients with LGG and the slow tumor growth rate. However, accumulation of the oncometabolite D-2-hydroxyglutarate (D-2HG) in IDH-mutated gliomas leads to suppression of inflammatory pathways in the tumor microenvironment, thereby contributing to the 'cold' tumor phenotype. Inhibiting D-2HG production presents an opportunity to generate a robust antitumor response following tumor antigen vaccination and immune checkpoint blockade.
    METHODS: An IDH1R132H glioma model was created in syngeneic HLA-A2/HLA-DR1-transgenic mice, allowing us to evaluate the vaccination with the human leukocyte antigens (HLA)-DR1-restricted, IDH1R132H mutation-derived neoepitope. The effects of an orally available inhibitor of mutant IDH1 and IDH2, AG-881, were evaluated as monotherapy and in combination with the IDH1R132H peptide vaccination or anti-PD-1 immune checkpoint blockade.
    RESULTS: The HLA-A2/HLA-DR1-syngeneic IDH1R132H cell line expressed the IDH1 mutant protein and formed D-2HG producing orthotopic gliomas in vivo. Treatment of tumor-bearing mice with AG-881 resulted in a reduction of D-2HG levels in IDH1R132H glioma cells (10 fold) and tumor-associated myeloid cells, which demonstrated high levels of intracellular D-2HG in the IDH1R132H gliomas. AG-881 monotherapy suppressed the progression of IDH1R132H gliomas in a CD4+ and CD8+ cell-dependent manner, enhanced proinflammatory IFNγ-related gene expression, and increased the number of CD4+ tumor-infiltrating T-cells. Prophylactic vaccination with the HLA-DR1-restricted IDH1R132H peptide or tumor-associated HLA-A2-restricted peptides did not enhance survival of tumor-bearing animals; however, vaccination with both HLA-A2-IDH1R132H and DR1-IDH1R132H peptides in combination with the IDH inhibitor significantly prolonged survival. Finally, tumor-bearing mice treated with both AG-881 and a PD-1 blocking antibody demonstrated improved survival when compared with either treatment alone.
    CONCLUSION: The development of effective IDH1R132H-targeting vaccine may be enhanced by integration with HLA class I-restricted cytotoxic T cell epitopes and AG-881. Our HLA-A2/HLA-DR1-syngeneic IDH1R132H glioma model should allow us to evaluate key translational questions related to the development of novel strategies for patients with IDH-mutant glioma.
    Keywords:  Brain Neoplasms; Central Nervous System Neoplasms; Drug Evaluation, Preclinical; Programmed Cell Death 1 Receptor; Vaccination
    DOI:  https://doi.org/10.1136/jitc-2022-004644
  15. Neuro Oncol. 2022 May 23. pii: noac132. [Epub ahead of print]
    Multi-institutional study of the frequency, genomic landscape and outcome of IDH-mutant glioma in paediatrics.
    Kee Kiat Yeo, Sanda Alexandrescu, Jennifer A Cotter, Jayne Vogelzang, Varun Bhave, Marilyn M Li, Jianling Ji, Jamal K Benhamida, Marc K Rosenblum, Tejus A Bale, Nancy Bouvier, Kristiyana Kaneva, Tom Rosenberg, Mary-Jane Lim Fat, Hia Ghosh, Migdalia Martinez, Dolly Aguilera, Amy Smith, Stewart Goldman, Eli L Diamond, Igor Gavrilovic, Tobey J MacDonald, Matthew D Wood, Kellie J Nazemi, Ai Lien Truong, Andrew Cluster, Keith L Ligon, Kristina Cole, Wenya Linda Bi, Ashley S Margol, Matthias A Karajannis, Karen D Wright.
       BACKGROUND: The incidence and biology of IDH1/2 mutations in pediatric gliomas are unclear. Notably, current treatment approaches by pediatric and adult providers vary significantly. We describe the frequency and clinical outcomes of IDH1/2-mutant gliomas in pediatrics.
    METHODS: We performed a multi-institutional analysis of the frequency of pediatric IDH1/2-mutant gliomas, identified by next-generation sequencing (NGS). In parallel, we retrospectively reviewed pediatric IDH1/2-mutant gliomas, analyzing clinico-genomic features, treatment approaches, and outcomes.
    RESULTS INCIDENCE: Among 851 patients with pediatric glioma who underwent NGS, we identified 78 with IDH1/2 mutations. Among patients 0-9 and 10-21 years old, 2/378 (0.5%) and 76/473 (16.1%) had IDH1/2-mutant tumors, respectively. Frequency of IDH mutations was similar between low- (52/570, 9.1%) and high-grade glioma (25/277, 9.0%). Four tumors were graded as intermediate histologically, with one IDH1 mutation.
    OUTCOME: Seventy-six patients with IDH1/2-mutant glioma had outcome data available. Eighty-four percent of patients with low-grade glioma were managed observantly without additional therapy. For low-grade astrocytoma, 5-year progression-free survival (PFS) was 42.9% (95%CI:20.3-63.8) and, despite excellent short-term overall survival (OS), numerous disease-related deaths after year 10 were reported. Patients with high-grade astrocytoma had a 5-year PFS/OS of 36.8% (95%CI:8.8-66.4) and 84% (95%CI:50.1-95.6), respectively. Patients with oligodendroglioma had excellent OS.
    CONCLUSIONS: A subset of pediatric gliomas are driven by IDH1/2 mutations, with a higher rate among adolescents. The majority of patients underwent upfront observant management without adjuvant therapy. Findings suggest that the natural history of pediatric IDH1/2-mutant glioma may be similar to that of adults, though additional studies are needed.
    Keywords:  Frequency; Glioma; IDH1/2 mutation; Outcomes; Pediatrics
    DOI:  https://doi.org/10.1093/neuonc/noac132
  16. Neuro Oncol. 2022 May 23. pii: noac141. [Epub ahead of print]
    Therapeutic targeting of prenatal pontine ID1 signaling in diffuse midline glioma.
    Dana Messinger, Micah K Harris, Jessica R Cummings, Chase Thomas, Tao Yang, Stefan R Sweha, Rinette Woo, Robert Siddaway, Martin Burkert, Stefanie Stallard, Tingting Qin, Brendan Mullan, Ruby Siada, Ramya Ravindran, Michael Niculcea, Abigail Dowling, Joshua Bradin, Kevin F Ginn, Melissa A H Gener, Kathleen Dorris, Nicholas A Vitanza, Susanne V Schmidt, Jasper Spitzer, Li Jiang, Mariella G Filbin, Xuhong Cao, Maria G Castro, Pedro R Lowenstein, Rajen Mody, Arul Chinnaiyan, Pierre-Yves Desprez, Sean McAllister, Matthew D Dun, Cynthia Hawkins, Sebastian M Waszak, Sriram Venneti, Carl Koschmann, Viveka Nand Yadav.
       BACKGROUND: Diffuse midline gliomas (DMG) are highly invasive brain tumors with rare survival beyond two years past diagnosis and limited understanding of the mechanism behind tumor invasion. Previous reports demonstrate upregulation of the protein ID1 with H3K27M and ACVR1 mutations in DMG, but this has not been confirmed in human tumors or therapeutically targeted.
    METHODS: Whole exome, RNA, and ChIP-sequencing was performed on the ID1 locus in DMG tissue. Scratch-assay migration and transwell invasion assays of cultured cells were performed following shRNA-mediated ID1-knockdown. In vitro and in vivo genetic and pharmacologic [cannabidiol (CBD)] inhibition of ID1 on DMG tumor growth was assessed. Patient-reported CBD dosing information was collected.
    RESULTS: Increased ID1 expression in human DMG and in utero electroporation (IUE) murine tumors is associated with H3K27M mutation and brainstem location. ChIP-sequencing indicates ID1 regulatory regions are epigenetically active in human H3K27M-DMG tumors and prenatal pontine cells. Higher ID1-expressing astrocyte-like DMG cells share a transcriptional program with oligo/astrocyte-precursor cells (OAPCs) from the developing human brain and demonstrate upregulation of the migration regulatory protein SPARCL1. Genetic and pharmacologic (CBD) suppression of ID1 decreases tumor cell invasion/migration and tumor growth in H3.3/H3.1K27M PPK-IUE and human DIPGXIIIP* in vivo models of pHGG. The effect of CBD on cell proliferation appears to be non-ID1 mediated. Finally, we collected patient-reported CBD treatment data, finding that a clinical trial to standardize dosing may be beneficial.
    CONCLUSIONS: H3K27M-mediated re-activation of ID1 in DMG results in a SPARCL1+ migratory transcriptional program that is therapeutically targetable with CBD.
    Keywords:  CBD; DMG; ID1; ROS; invasion/migration
    DOI:  https://doi.org/10.1093/neuonc/noac141
  17. Neurooncol Pract. 2022 May;9(3): 193-200
    A randomized feasibility study evaluating temozolomide circadian medicine in patients with glioma.
    Anna R Damato, Ruth G N Katumba, Jingqin Luo, Himachandana Atluri, Grayson R Talcott, Ashwin Govindan, Emily A Slat, Katherine N Weilbaecher, Yu Tao, Jiayi Huang, Omar H Butt, George Ansstas, Tanner M Johanns, Milan G Chheda, Erik D Herzog, Joshua B Rubin, Jian L Campian.
       Background: Gliomas are the most common primary brain tumor in adults. Current treatments involve surgery, radiation, and temozolomide (TMZ) chemotherapy; however, prognosis remains poor and new approaches are required. Circadian medicine aims to maximize treatment efficacy and/or minimize toxicity by timed delivery of medications in accordance with the daily rhythms of the patient. We published a retrospective study showing greater anti-tumor efficacy for the morning, relative to the evening, administration of TMZ in patients with glioblastoma. We conducted this prospective randomized trial to determine the feasibility, and potential clinical impact, of TMZ chronotherapy in patients with gliomas (NCT02781792).
    Methods: Adult patients with gliomas (WHO grade II-IV) were enrolled prior to initiation of monthly TMZ therapy and were randomized to receive TMZ either in the morning (AM) before 10 am or in the evening (PM) after 8 pm. Pill diaries were recorded to measure compliance and FACT-Br quality of life (QoL) surveys were completed throughout treatment. Study compliance, adverse events (AE), and overall survival were compared between the two arms.
    Results: A total of 35 evaluable patients, including 21 with GBM, were analyzed (18 AM patients and 17 PM patients). Compliance data demonstrated the feasibility of timed TMZ dosing. There were no significant differences in AEs, QoL, or survival between the arms.
    Conclusions: Chronotherapy with TMZ is feasible. A larger study is needed to validate the effect of chronotherapy on clinical efficacy.
    Keywords:  chronotherapy; feasibility; gliomas; quality of life
    DOI:  https://doi.org/10.1093/nop/npac003
  18. Nat Immunol. 2022 May 27.
    Mapping the tumor-infiltrating immune cells during glioblastoma progression.
    Senthilnath Lakshmanachetty, Siddhartha S Mitra.
      
    DOI:  https://doi.org/10.1038/s41590-022-01223-0
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