bims-malgli 2025-09-14 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2025–09–14
twelve papers selected by
Oltea Sampetrean, Keio University

Lomitapide enhances cytotoxic effects of temozolomide in chemotherapy-resistant glioblastoma.
Immunologic specificity in glioblastoma: Antigen discovery and translational implications.
Hydrogen sulfide inhibits recruitment of monocyte-derived tumor associated macrophages in glioblastoma by downregulating CXCL12.
Translational advancements in tumor vaccine therapies for glioblastomas.
The glioma microenvironment and its impact on antitumor immunity.
Perturbing neural stem cell fate in glioblastoma heterogeneity and beyond.
Cellular immunotherapies for central nervous system cancers.
Advances in neuroscientific mechanisms and therapies for glioblastoma.
Window of opportunity evaluation of blood-brain barrier permeability heterogeneity within and across high-grade glioma patients.
Within and beyond the tumor: Mechanisms of glioblastoma-induced immunosuppression.
Extrachromosomal DNA-Driven Oncogene Spatial Heterogeneity and Evolution in Glioblastoma.
Multicellular tumor-stromal interactions recapitulate aspects of therapeutic response and human oncogenic signaling in a 3D disease model for H3K27M-altered DIPG.

JCI Insight. 2025 Sep 09. pii: e186703. [Epub ahead of print]10(17):

Lomitapide enhances cytotoxic effects of temozolomide in chemotherapy-resistant glioblastoma.

Alyona Ivanova, Taylor M Wilson, Kimia Ghannad-Zadeh, Esmond Tse, Robert Flick, Megan Wu, Sunit Das.

  More than a third of patients with glioblastoma experience tumor progression during adjuvant therapy. In this study, we performed a high-throughput drug repurposing screen of FDA-approved agents capable of crossing the blood-brain barrier in order to find agents to counteract acquired or inherent glioma cell resistance to temozolomide-associated cytotoxicity. We identified the cholesterol processing inhibitor, lomitapide, as a potential chemosensitizer in glioblastoma. In vitro treatment of temozolomide-resistant glioblastoma cells with lomitapide resulted in decreased intracellular ubiquinone levels and sensitized cells to temozolomide-induced ferroptosis. Concomitant treatment with lomitapide and temozolomide (TMZ) prolonged survival and delayed tumor recurrence in a mouse glioblastoma model, compared with treatment xwith TMZ alone. Our data identified lomitapide as a potential adjunct for treatment of temozolomide-resistant glioblastoma.

Keywords:  Brain cancer; Cell biology; Clinical practice; Drug therapy; Oncology

DOI:  https://doi.org/10.1172/jci.insight.186703
Neurooncol Adv. 2025 Sep;7(Suppl 4): iv41-iv70

Immunologic specificity in glioblastoma: Antigen discovery and translational implications.

Cameron M Hill, Anthony Z Wang, Brian Hsueh, Ramiro Ramirez, Ngima Sherpa, Marcelo Costa, Ofir Williams, Mao Li, Gavin P Dunn.

  Recent studies have highlighted the therapeutic potential of targeting tumor antigens (TAs) in glioblastoma (GBM). Several classes of TAs, such as tumor-associated, cancer testis, and tumor-specific antigens, have proven to be immunogenic and used safely in vaccines. Many of these vaccines have focused on tumor-associated or cancer testis antigens. However, tumor-specific antigens (TSA) present an ideal target due to the lack of tolerance and exclusive tumor expression, mitigating the risk of off-target effects. Most research on TSAs in GBM has aimed to uncover neoantigens, yet the dearth of shared neoantigens as well as the cost and labor-intensive process of identifying personal neoantigens have acted as barriers to treatment. A better understanding of the individual antigens spanning all three TA classes is important to improve the design of GBM antigen therapies and understand, fundamentally, the nature of immunologic specificity in glioma. We review the antigen classes in all cancers and how TAs are discovered. Then, we focus on the unique properties of GBM and the antigens that have been identified and used for therapy in GBM. Finally, we discuss translational considerations for future antigen-targeted treatments.

Keywords:  glioblastoma; immunotherapy; neoantigens; tumor antigens; tumor specificity

DOI:  https://doi.org/10.1093/noajnl/vdaf028
Redox Biol. 2025 Sep 08. pii: S2213-2317(25)00379-9. [Epub ahead of print]86 103866

Hydrogen sulfide inhibits recruitment of monocyte-derived tumor associated macrophages in glioblastoma by downregulating CXCL12.

Joseph Camarano, Morgan Roque, Gabrielle Gahn, Stephen Garrett Whipple, Danielle Terrell, Charles Ronkon, Jamie Toms, Anthony Sin, Bharat Guthikonda, Khatri Latha, Yuhui Yang, Xinggui Shen, Christopher G Kevil, Ganesh Rao, Sungho Lee.

  Tumor associated macrophages (TAMs) directly contribute to the dismal prognosis of glioblastoma by preventing anti-tumor immunity and promoting tumor invasion and angiogenesis. Inhibiting TAM infiltration is a potential therapeutic strategy in glioblastoma, with several chemokine antagonists in early clinical development. Hydrogen sulfide, a gasotransmitter that regulates microglial accumulation in a wide range of CNS diseases, may be a novel therapeutic target to prevent TAM recruitment in glioblastoma. In this study, hydrogen sulfide concentrations were directly measured from 14 isocitrate dehydrogenase (IDH)-wildtype glioblastoma surgical samples and compared against overall survival as well as expression of TAM markers and chemokines. Effects of hydrogen sulfide donor therapy on survival and TAM recruitment were also examined in a genetically engineered mouse model of glioblastoma. High hydrogen sulfide concentrations conferred a survival benefit in IDH-wildtype glioblastoma, in association with reduced monocyte-derived TAM density and downregulation of CXCL12. These findings were validated by administering hydrogen sulfide donor SG1002 to an immunocompetent mouse model of glioblastoma, which improved survival, inhibited monocyte infiltration, and downregulated CXCL12. Finally, hydrogen sulfide donor treatment directly reduced CXCL12 expression in glioblastoma cells, diminishing their ability to recruit monocytes in vitro. Taken together, these results demonstrate that hydrogen sulfide signaling prevents monocyte-derived TAM accumulation in glioblastoma by inhibiting chemotaxis.

Keywords:  Glioblastoma; Hydrogen sulfide; Tumor associated macrophage

DOI:  https://doi.org/10.1016/j.redox.2025.103866
Neurooncol Adv. 2025 Sep;7(Suppl 4): iv72-iv83

Translational advancements in tumor vaccine therapies for glioblastomas.

Rohan Jha, Lennard Spanehl, Jason A Chen, Florian A Gessler, Omar Arnaout, Pablo A Valdes, Bryan D Choi, Pier Paolo Peruzzi, Joshua D Bernstock, Ennio A Chiocca.

  Glioblastoma (GBM) presents significant therapeutic challenges due to the limited efficacy of current treatments. This resistance is multifactorial, stemming from tumor heterogeneity, an immunosuppressive tumor microenvironment, and the restrictive blood-brain barrier, which limits therapeutic access. In response, immunotherapies, particularly tumor vaccines, have emerged as strategies to harness the immune system against these tumors. This review provides an overview of recent advancements and notable clinical trials in tumor vaccine development for GBM. Additionally, it discusses recent preclinical advancements focused on enhancing immune recruitment and response. Identified strategies include peptide, cellular, and nucleic acid vaccines targeting tumor-specific antigens to induce antitumor T-cell responses. Clinical data and preclinical studies exploring various vaccine candidates, adjuvants, and delivery methods demonstrate encouraging results, with some showing improved progression-free and overall survival rates. Despite these advancements, it is clear that further research into personalized vaccines and combination therapies is necessary to enhance immune responses and improve clinical outcomes.

Keywords:  clinical trials; glioblastoma (GBM); high-grade gliomas; personalized vaccines; vaccine; vaccine adjuvants

DOI:  https://doi.org/10.1093/noajnl/vdaf051
Neurooncol Adv. 2025 Sep;7(Suppl 4): iv19-iv31

The glioma microenvironment and its impact on antitumor immunity.

Landon J Hansen, Christopher M Jackson.

  Gliomas are a heterogeneous group of intrinsic brain tumors that are among the most difficult cancers to treat. Diffuse invasion into normal brain tissue prevents complete surgical resection; therefore, adjuvant therapy is necessary to curtail tumor progression and recurrence. High-grade, isocitrate dehydrogenase wild-type gliomas, also known as glioblastomas, are particularly resistant to treatment. Despite aggressive therapy with maximal safe resection, radiation, and chemotherapy, the median survival remains less than 2 years and has changed little in the past 2 decades. A major focus of therapeutic development for cancer treatment is immunotherapy, which aims to enhance the immune system's ability to destroy tumor cells wherever they reside. While cancer immunotherapy has dramatically improved outcomes for patients with advanced melanoma, lung cancer, and many other malignancies, immunotherapies have not yet demonstrated the ability to reliably improve survival for glioblastoma patients. One of the fundamental challenges to developing effective immunotherapy for glioblastoma is the heterogenous and complex tumor microenvironment (TME), where there are multiple anatomic, molecular, and functional barriers to generating and sustaining antitumor immunity. Recent insights into the contributions of specific components of the glioma tumor microenvironment are leading the way from a trial-and-error approach to rationally targeted combination therapies. In this focused review, we discuss specific characteristics of the TME that impede immunotherapy for glioma and approaches in various stages of development aimed at overcoming these barriers.

Keywords:  Immunotherapy; anti-tumor immunity; immune checkpoints; tumor metabolism; tumor microenvironment

DOI:  https://doi.org/10.1093/noajnl/vdae204
Stem Cell Reports. 2025 Sep 09. pii: S2213-6711(25)00237-1. [Epub ahead of print]20(9): 102633

Perturbing neural stem cell fate in glioblastoma heterogeneity and beyond.

Ethan W Hollingsworth, Jaime Imitola.

Intratumoral heterogeneity in glioblastoma is thought to underlie its remarkable ability to recur and resist therapies. Its origins, however, remain unknown. In this issue, Liu et al. model the contributions of cell-of-origin and genetic drivers to intratumoral heterogeneity in glioblastoma, using a perturbation paradigm with broad neurodevelopmental applications.

DOI: https://doi.org/10.1016/j.stemcr.2025.102633
Neurooncol Adv. 2025 Sep;7(Suppl 4): iv84-iv94

Cellular immunotherapies for central nervous system cancers.

Brian J Scott, Michelle Monje.

  Cellular Immunotherapies have transformed therapeutic options for individuals with hematologic malignancies over the past 10 years. There are several distinct types of cellular immunotherapies, each with potential applications to CNS cancers. Here, we review cancer cellular therapeutics for cancers of the brain and spinal cord, focusing on the preclinical and clinical studies that have been done in glioblastoma, diffuse intrinsic pontine glioma/diffuse midline glioma, medulloblastoma and lymphoma involving the central nervous system. Numerous potential therapeutic targets have been identified, and several early clinical trials have demonstrated safety and feasibility of administering CAR T and CAR NK cells for intracranial tumors. Addressing mechanisms of treatment failure, while safely and effectively studying the most promising therapies will advance the treatment landscape for these extremely challenging diseases.

Keywords:  cellular immunotherapy; chimeric antigen receptor T cell; chimeric antigen receptor natural killer cell; diffuse intrinsic pontine glioma/diffuse midline glioma; glioblastoma

DOI:  https://doi.org/10.1093/noajnl/vdaf120
iScience. 2025 Sep 19. 28(9): 113347

Advances in neuroscientific mechanisms and therapies for glioblastoma.

Ke Li, Mengyuan Duan, Qian Lu, Jiaqi Liu, Maotao He, Yunxiang Zhang.

  Gliomas are common primary brain tumors in the central nervous system, characterized by invasiveness, heterogeneity, and drug resistance, posing a threat to patients' lives. Glioblastoma (IDH wild-type) exhibits the highest invasiveness and mortality rate, making it a challenging therapeutic target. This review first outlines the characteristics of gliomas and their impact on the nervous system, then explores the pathological mechanisms and unique behaviors of glioblastoma (IDH wild-type), as well as the influence of the nervous system on its occurrence and progression. In terms of treatment, potential targeted strategies are summarized, and the potential of novel precision therapies, such as immunotherapy and gene therapy, is evaluated. This article underscores the importance of understanding the complex interactions between the nervous system and gliomas, offering new perspectives and targets for treatment. Future research should elucidate these interactions to identify more effective therapeutic targets and improve patient prognosis and quality of life.

Keywords:  neurology; oncology

DOI:  https://doi.org/10.1016/j.isci.2025.113347
Neuro Oncol. 2025 Sep 06. pii: noaf204. [Epub ahead of print]

Window of opportunity evaluation of blood-brain barrier permeability heterogeneity within and across high-grade glioma patients.

Ju-Hee Oh, Sarah K Reed, Cecile Riviere-Cazaux, Minjee Kim, Ann C Mladek, Silvia M Illamola, Wenjuan Zhang, Rachael A Vaubel, Alissa Caron, Michael S Regan, Angela K Birnbaum, Afroz Mohammad, Wenqiu Zhang, Jesse G Dixon, Timothy J Kaufmann, Leland S Hu, Daniel J Ma, Sani Kizilbash, Nathalie Y R Agar, Caterina Giannini, Susan M Geyer, Ian F Parney, Evanthia Galanis, Terry C Burns, William F Elmquist, Jann N Sarkaria.

   BACKGROUND: Disruption of the blood-brain barrier (BBB) in high-grade brain tumors is characterized by contrast accumulation on diagnostic imaging. This window of opportunity study correlates contrast imaging features with the tumor distribution of BBB-permeable (levetiracetam) and -impermeable (cefazolin) drugs.
METHODS: Patients with a clinical diagnosis of a high-grade brain tumor underwent MRI for surgical planning. Cefazolin and levetiracetam were administered prior to skin incision, and serial plasma and image-registered tumor samples were collected during the operation. Drug levels were measured by LC-MS/MS, tissue drug levels were corrected for residual blood, and tumor-to-plasma concentration ratios were calculated. Intraoperative microdialysis was performed in a subset of patients to measure the same two drugs.
RESULTS: Tumor (n=125) and plasma (n=261) samples were available for analysis from 42 operative cases. Across all samples, the tumor-to-plasma ratio was significantly lower for cefazolin (marginal mean (MM): 0.15, 95% CI: 0.11-0.19) as compared to levetiracetam (MM: 0.70, 95% CI: 0.64-0.75; p<0.001). When compared between contrast-enhancing and non-enhancing regions, tumor-to-plasma ratios for cefazolin varied by 4.4-fold (0.27, 95% CI: 0.20-0.35 vs. 0.06, 95% CI: 0.04-0.08, respectively; p<0.001), and varied for levetiracetam by 1.4-fold (0.88, 95% CI: 0.78-0.97 vs. 0.61, 95% CI: 0.55-0.66, respectively; p<0.001). These results were confirmed with the intra-operative microdialysis and a population pharmacokinetic analysis.
CONCLUSIONS: This study demonstrates significant inter- and intra-tumoral heterogeneity in drug delivery for both levetiracetam and cefazolin within high-grade brain tumors that is not necessarily predicted by clinical MR-imaging and may reflect tumor-induced changes in both perfusion and BBB integrity.

Keywords:  High-grade glioma; blood-brain barrier; glioblastoma; magnetic resonance imaging; window of opportunity

DOI:  https://doi.org/10.1093/neuonc/noaf204
Neurooncol Adv. 2025 Sep;7(Suppl 4): iv4-iv18

Within and beyond the tumor: Mechanisms of glioblastoma-induced immunosuppression.

Bhairavy J Puviindran, Shannon Wallace, Katayoun Ayasoufi, Emily Lerner, Peter E Fecci.

  Immunotherapies have thus far proved of limited efficacy against glioblastoma. Failures can be attributed to a host of immunosuppressive mechanisms that are either directly employed by the tumor or are instead a convenient feature of the intracranial environment. This review aims to categorize glioblastoma immune-evasive tendencies, provide an update on our understanding of etiologies, and describe newer approaches to improving therapeutic responses.

Keywords:  T cell exhaustion; glioblastoma; immune checkpoint blockade; immunosuppression

DOI:  https://doi.org/10.1093/noajnl/vdaf006
Cancer Discov. 2025 Sep 08. OF1-OF18

Extrachromosomal DNA-Driven Oncogene Spatial Heterogeneity and Evolution in Glioblastoma.

Imran Noorani, Magnus Haughey, Jens Luebeck, Andrew Rowan, Eva Grönroos, Francesco Terenzi, Ivy Tsz-Lo Wong, Davide Pradella, Marta Lisi, Jeanette Kittel, Natasha Sharma, Chris Bailey, Clare E Weeden, Donald M Bell, Eric Joo, Vittorio Barbè, Matthew G Jones, King L Hung, Emma L Nye, Mary Green, Lucy Meader, Emma J Norton, Mark Fabian, Nnennaya Kanu, Mariam Jamal-Hanjani, Thomas Santarius, Andrea Ventura, James A R Nicoll, Delphine Boche, Howard Y Chang, Vineet Bafna, Weini Huang, Paul S Mischel, Charles Swanton, Benjamin Werner.

Oncogenes amplified on extrachromosomal DNA (ecDNA) contribute to treatment resistance and poor survival across cancers. Currently, the spatiotemporal evolution of ecDNA remains poorly understood. In this study, we integrate computational modeling with samples from 94 treatment-naive human glioblastomas (GBM) to investigate the spatiotemporal evolution of ecDNA. We observe oncogene-specific patterns of ecDNA spatial heterogeneity, emerging from random ecDNA segregation and differing fitness advantages. Unlike PDGFRA-ecDNAs, EGFR-ecDNAs often accumulate prior to clonal expansions, conferring strong fitness advantages and reaching high abundances. In corroboration, we observe pretumor ecDNA accumulation in vivo in genetically engineered mouse neural stem cells. Variant and wild-type EGFR-ecDNAs often coexist in GBM. Those variant EGFR-ecDNAs, most commonly EGFRvIII-ecDNA, always derive from preexisting wild-type EGFR-ecDNAs, occur early, and reach high abundance. Our results suggest that the ecDNA oncogenic makeup determines unique evolutionary trajectories. New concepts such as ecDNA clonality and heteroplasmy require a refined evolutionary interpretation of genomic data in a large subset of GBMs.
SIGNIFICANCE: We study spatial patterns of ecDNA-amplified oncogenes and their evolutionary properties in human GBM, revealing an ecDNA landscape and ecDNA oncogene-specific evolutionary histories. ecDNA accumulation can precede clonal expansion, facilitating the emergence of EGFR oncogenic variants, reframing our interpretation of genomic data in a large subset of GBMs. See related article by Korsah et al., p. XX.

DOI: https://doi.org/10.1158/2159-8290.CD-24-1555
Oncogene. 2025 Sep 06.

Multicellular tumor-stromal interactions recapitulate aspects of therapeutic response and human oncogenic signaling in a 3D disease model for H3K27M-altered DIPG.

Meenakshi Upreti, Astgik Petrosyan, Matthew E Thornton, Anahit Hovsepyan, G Esteban Fernandez, David S Koos, Stephanie D Byrum, Samuel G Mackintosh, Jacob K Al-Husseini, Tania Porras, Joseph Ha, Alan J Tackett, Miqin Zhang, Malkiat S Johal, Anat Erdreich-Epstein, Susan Durham, Mark D Krieger, Ashley S Margol, Brendan H Grubbs, Timothy C Chambers, Shahab Asgharzadeh, Rex A Moats, Peter A Chiarelli.

It has become evident from decades of clinical trials that multimodal therapeutic approaches with focus on cell intrinsic and microenvironmental cues are needed to improve understanding and treat the rare, inoperable, and ultimately fatal diffuse intrinsic pontine glioma (DIPG), now categorized as a diffuse midline glioma. In this study we report the development and characterization of an in vitro system utilizing 3D Tumor Tissue Analogs (TTA), designed to replicate the intricate DIPG microenvironment. The innate ability of fluorescently labeled human brain endothelial cells, microglia, and patient-derived DIPG cell lines to self-assemble has been exploited to generate multicellular 3D TTAs that mimic tissue-like microstructures, enabling an in- depth exploration of the spatio-temporal dynamics between neoplastic and stromal cells. The 3D-TTA model recapitulates clinical patterns of DIPG growth, evidenced by resistance to chemotherapy, HDAC and proteasome inhibitors, as well as sensitization to the antibody-activated innate immune microenvironment including complement proteins and surrounding microglia. Multimodal fluorescence imaging platforms integrated with high-throughput omics revealed that alterations in tumor cell motility and growth in the 3D-TTA model compared to tumor cell only spheroids correlated with specific transcriptomic and proteomic changes. STAT3, ITGA5, LGALS1, SOD2, MVP, and CLIC1, associated with microenvironment signaling, DNA replication, and immune regulation, were identified as potential novel targets in the 3D model. The results indicate that the 3D TTA platform developed here represents a powerful tool for preclinical studies, paving the way for identification/validation of tissue specific biomarkers and novel drug targets, thus advancing disease management strategies for DIPG in children.

DOI: https://doi.org/10.1038/s41388-025-03533-7