bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2025–11–16
nine papers selected by
Oltea Sampetrean, Keio University
  1. Glioblastoma biopsy reveals treatment response.
  2. Engineered CXCR3-A expression enhances B7-H3-targeting CAR T cell migration and efficacy against diffuse intrinsic pontine glioma.
  3. Amide proton transfer-weighted (APTw) CEST MRI in clinical routine for single time point diagnosis of pseudoprogression in IDH-wildtype glioblastoma.
  4. Cysteine addiction in drug resistant glioblastoma and therapeutic targeting with designer selenium compounds.
  5. Single-cell proteomics sheds light on neutrophil diversity in glioblastoma.
  6. Opposing Functions of White Matter in Glioblastoma.
  7. Characterization of the tumor microbiome of brain metastases and glioblastoma reveals tumor-type-specific and location-specific microbial signatures.
  8. Phase II study of safusidenib erbumine in patients with chemotherapy- and radiotherapy-naïve isocitrate dehydrogenase 1-mutated WHO grade 2 gliomas.
  9. Single nucleus transcriptomics, pharmacokinetics, and pharmacodynamics of CDK4/6 and mTOR inhibition in a phase 0/1 trial of recurrent high-grade glioma.
  1. Nat Rev Neurol. 2025 Nov 11.
    Glioblastoma biopsy reveals treatment response.
    Ian Fyfe.
      
    DOI:  https://doi.org/10.1038/s41582-025-01168-6
  2. Nat Commun. 2025 Nov 11. 16(1): 9914
    Engineered CXCR3-A expression enhances B7-H3-targeting CAR T cell migration and efficacy against diffuse intrinsic pontine glioma.
    Edward Z Song, Andrea Timpanaro, Michael Meechan, Leonel Elena-Sanchez, Lucy Z Li, Sophie Jamet, Davina S Lau, Lily I Winter, Matthew D Dun, Jessica B Foster, Myron K Evans, Siobhan S Pattwell, Vandana Kalia, Surojit Sarkar, Michael C Jensen, Matthew C Biery, Nicholas A Vitanza.
      Diffuse intrinsic pontine glioma (DIPG) is a fatal brainstem tumor desperately in need of better treatments. Chimeric antigen receptor (CAR) T cell therapies for DIPG have demonstrated clinical tolerability and bioactivity, but not universal benefit. A major obstacle is insufficient CAR T cell trafficking to the tumor. As our recent clinical trials have demonstrated locoregional elevation of CXCL10, a ligand of the chemokine receptor CXCR3, here we aim to leverage this CXCL10 upregulation to enhance cell trafficking by engineering our B7-H3-targeting CAR T cells to overexpress CXCR3 variants. We demonstrate that, compared to unmodified B7-H3 CAR T cells, CXCR3-A-modified CAR T cells migrate more efficiently toward CXCR3 ligands in vitro, and when delivered intracerebroventricularly in orthotopic DIPG mouse models, CXCR3-A-modified CAR T cells show enhanced trafficking into the tumor and improved therapeutic efficacy. Overall, our data support the potential for engineering CXCR3-A expression to enhance CAR T cell trafficking and efficacy against DIPG.
    DOI:  https://doi.org/10.1038/s41467-025-64861-6
  3. Neuro Oncol. 2025 Nov 13. pii: noaf261. [Epub ahead of print]
    Amide proton transfer-weighted (APTw) CEST MRI in clinical routine for single time point diagnosis of pseudoprogression in IDH-wildtype glioblastoma.
    Thomas Zeyen, Inga Krause, Andreas Decker, Florian Kroh, Sebastian Regnery, Johannes Weller, Niklas Schaefer, Mousa Zidan, Anna-Laura Potthoff, Matthias Schneider, Lea L Friker, Jochen Keupp, Christoph Katemann, Julian P Layer, Christina Schaub, Eleni Gkika, Hartmut Vatter, Torsten Pietsch, Alexander Radbruch, Ulrich Herrlinger, Daniel Paech.
       BACKGROUND: Differentiating progressive disease (PD) from treatment-related effects (TRE) in glioblastoma remains challenging, particularly at single time point evaluations. TRE can occur at any disease stage, and its underlying biology is poorly understood. This study evaluates the clinical feasibility and diagnostic performance of amide proton transfer-weighted (APTw) MRI in this challenge.
    METHODS: Following the integration of APTw MRI into the routine clinical workflow for brain tumor imaging, we screened a total of 870 scans from 626 patients. APTw signal (voxel-based measurement) was automatically quantified in gadolinium-enhanced T1w and FLAIR regions of interest using a deep learning-based approach for 3D tumor segmentations. PD and TRE were compared using unpaired t-tests, and diagnostic accuracy was assessed via ROC- and logistic regression analysis.
    RESULTS: Among 256 MRI scans of 143 patients with glioblastoma, 65 scans showed PD (n = 42) or TRE (n = 23). The median APTw signal was higher in PD (2.23%) vs TRE (1.76%; p = 0.001). ROC analysis showed an area under the curve (AUC) of 0.82. In patients with early PD or TRE (<6 months post-radiotherapy), the AUC increased to 0.93. Anti-angiogenic therapy decreased APTw signal (p < 0.01). Combining APTw MRI with DWI and PWI improved diagnostic accuracy (AUC = 0.90).
    CONCLUSIONS: APTw MRI is a non-invasive imaging tool that is feasible for clinical routine and aids in differentiation of early progression from pseudoprogression in glioblastoma. Its diagnostic accuracy decreases with application of anti-angiogenic treatment and at later follow-up time points. Highest diagnostic accuracy was found in a multimodal approach combining APTw MRI, PWI and DWI.
    Keywords:  amide proton transfer-weighted imaging; chemical exchange saturation transfer imaging; glioblastoma; pseudoprogression
    DOI:  https://doi.org/10.1093/neuonc/noaf261
  4. Neuro Oncol. 2025 Nov 10. pii: noaf265. [Epub ahead of print]
    Cysteine addiction in drug resistant glioblastoma and therapeutic targeting with designer selenium compounds.
    Deanna Tiek, Xiao Song, Runxin Wu, Xiaozhou Yu, Maya Walker, Yingyu Mao, Derek Sisbarro, Qiu He, Assa Magassa, Amandeep Singh, Junxuan Lu, Arun K Sharma, Jason Miska, Bo Hu, Marcelo G Bonini, Xiaoyu Zhang, Shi-Yuan Cheng.
       BACKGROUND: Cysteine is a multifunctional amino acid that can be oxidized affecting disulfide bond formation, redox signaling, and protein function. Reactive oxygen species (ROS) and the metabolic environment dictate cysteine uptake and oxidation status - especially in redox sensitive pathways. As many chemotherapeutic agents increase ROS, including the standard for glioblastoma (GBM), temozolomide (TMZ), we hypothesized that TMZ-resistant (TMZ-R) GBM would have increased ROS affecting cysteine reactivity that could be therapeutically targeted.
    METHODS: Here, to study the metabolic state within drug sensitive and resistant GBM, we used metabolite tracing with 13C-Cyst(e)ine, specialized cysteine reactivity proteomics and CRISPR screening with drug treatments to determine the efficacy of targeting cysteine metabolic pathways with our designer selenium drug in both patient derived cell lines and patient derived xenograft GBM orthotopic models.
    RESULTS: We show that TMZ-R have increased cyst(e)ine uptake, cysteine reactivity, and sensitivity to selenium (Se)-containing compounds - which can bind cysteine - in vitro and in vivo. We show that in TMZ-R models selenium compound treatment increases the need for thioredoxin reductases where co-treatment of Se compounds and the thioredoxin inhibitor auranofin significantly improves overall survival in mouse models.
    CONCLUSIONS: Overall, our findings show a unique metabolic environment in TMZ-R models where designer brain penetrant Se-containing compounds target cysteine reactivity within proteins necessary for cancer cell survival and hold therapeutic potential.
    Keywords:  Glioblastoma; TMZ resistance; cysteine oxidation; drug resistance; metabolism
    DOI:  https://doi.org/10.1093/neuonc/noaf265
  5. Nat Rev Immunol. 2025 Nov 11.
    Single-cell proteomics sheds light on neutrophil diversity in glioblastoma.
    Aglaia Skolariki, Eileen E Parkes.
      
    DOI:  https://doi.org/10.1038/s41577-025-01241-7
  6. Neuro Oncol. 2025 Nov 14. pii: noaf266. [Epub ahead of print]
    Opposing Functions of White Matter in Glioblastoma.
    Daniel J Silver, Gunnar H D Poplawski, Justin D Lathia.
      
    DOI:  https://doi.org/10.1093/neuonc/noaf266
  7. Nat Cancer. 2025 Nov 14.
    Characterization of the tumor microbiome of brain metastases and glioblastoma reveals tumor-type-specific and location-specific microbial signatures.
    Elinor Gigi, Nancy Gavert, Lilach Raijman-Nagar, Yaara Zwang, Hofit Zemach, Ilana Livyatan, Adva Levy-Barda, Yossi Laviv, Andrew A Kanner, Alexandra Amiel, Tali Siegal, Anca Leibovici, Inna Selezen, Omar Badran, Yaniv Zohar, Esraa Safadi, Lyndsey L Prather, Cassandra R Helfer, Patricia Castro, Iris Barshack, Tali Dadosh, Smadar Levin-Zaidman, Inna Goliand, Ofra Golani, Suzana Horn, Jacob J Mandel, Noam Shental, Ayelet Shai, Shlomit Yust-Katz, Ravid Straussman.
      Brain tumors, including glioblastoma multiforme (GBM) and brain metastases, present a notable clinical challenge. Recent research highlights the presence of intratumor bacteria across many tumor types, yet the microbiome of brain tumors remains largely underexplored. Here we show that the microbiome of 322 brain tumors differs markedly by tumor type and location. Using multiple approaches to visualize, culture and sequence bacterial communities, we found that brain metastases harbor higher bacterial richness and diversity than GBM, with distinct microbial compositions. Moreover, metastases in posterior brain regions exhibited greater diversity than those in anterior regions. Pathway analysis revealed enrichment of bacterial metabolic pathways associated with tumor spread and metastasis in brain metastases while GBM was enriched with pathways supporting alternative phosphorus use. These findings provide valuable insights into the microbial landscape of brain tumors, highlighting tumor-type-specific and location-specific variation and suggesting potential roles for bacteria in brain tumor biology.
    DOI:  https://doi.org/10.1038/s43018-025-01073-3
  8. Neuro Oncol. 2025 Nov 08. pii: noaf258. [Epub ahead of print]
    Phase II study of safusidenib erbumine in patients with chemotherapy- and radiotherapy-naïve isocitrate dehydrogenase 1-mutated WHO grade 2 gliomas.
    Yoshiki Arakawa, Ryuta Saito, Yonehiro Kanemura, Kazuhiko Mishima, Shunichi Koriyama, Yoshitaka Narita, Toshihiro Kumabe, Kazuya Motomura, Kazuhiko Sugiyama, Fumiyuki Yamasaki, Akitake Mukasa, Masayuki Kanamori, Daisuke Kuga, Motoo Nagane, Yasuyuki Kakurai, Koji Isobe, Hideo Nakamura.
       BACKGROUND: Gliomas are primary brain tumors arising from glial cells. WHO grade 2 gliomas are initially managed with surgery for diagnosis and tumor reduction. However, complete resection is difficult due to their infiltrative growth into the normal brain and the need to preserve brain function. Current treatment options for WHO grade 2 gliomas are limited. Isocitrate dehydrogenase 1 (IDH1) mutations are frequently observed in WHO grade 2 gliomas. Safusidenib erbumine is a selective inhibitor of mutant IDH1 with substantial blood-brain barrier penetration. This study aimed to investigate the efficacy and safety of safusidenib erbumine in patients with chemotherapy- and radiotherapy-naïve IDH1-mutated WHO grade 2 gliomas.
    METHODS: This phase II study implemented a multicenter, open-label, single-arm design and evaluated the efficacy and safety of safusidenib erbumine in 27 patients with chemotherapy- and radiotherapy-naïve IDH1-mutated WHO grade 2 gliomas (NCT04458272).
    RESULTS: The confirmed objective response rate according to the Response Assessment in Neuro-Oncology criteria for WHO grade 2 gliomas was 44.4%. Median progression-free survival was not reached, with an event-free probability of 87.9% at 24 months. The frequently reported treatment-emergent adverse events (TEAEs) by Medical Dictionary for Regulatory Activities Preferred Terms (reported in ≥ 40%) were alopecia (59.3%), arthralgia (55.6%), skin hyperpigmentation (48.1%), and alanine aminotransferase increased (40.7%). TEAEs were characterized as mostly grade 1 or 2. The incidence of treatment-related grade ≥3 TEAEs was 18.5%.
    CONCLUSIONS: Safusidenib erbumine is a potential treatment option for patients with chemotherapy- and radiotherapy-naïve IDH1-mutated WHO grade 2 gliomas.
    Keywords:  IDH1 inhibitor; chemotherapy- and radiotherapy-naïve; delayed recurrence and progression; grade 2 gliomas; safusidenib erbumine
    DOI:  https://doi.org/10.1093/neuonc/noaf258
  9. Neuro Oncol. 2025 Nov 08. pii: noaf257. [Epub ahead of print]
    Single nucleus transcriptomics, pharmacokinetics, and pharmacodynamics of CDK4/6 and mTOR inhibition in a phase 0/1 trial of recurrent high-grade glioma.
    Kevin C Johnson, An-Chi Tien, Jun Jiang, James McNamara, Yu-Wei Chang, Chelsea Montgomery, Anita DeSantis, Leonel Elena-Sanchez, Yoko Fujita, Seongho Kim, Avishay Spitzer, Paul Gabriel, William F Flynn, Elise T Courtois, Amy Hong, Jocelyn Harmon, Yoshie Umemura, Artak Tovmasyan, Jing Li, Shwetal Mehta, Roel G W Verhaak, Nader Sanai.
       BACKGROUND: Outcomes for adult patients with high-grade glioma (HGG) remain poor, necessitating new treatment strategies. Key challenges include poor drug penetration in the brain and malignant cell state plasticity. Phase 0 studies identify agents that achieve target modulation through pharmacologically relevant brain concentrations.
    METHODS: A Phase 0/1 clinical trial combined the two targeted inhibitors ribociclib (CDK4/6 inhibitor) and everolimus (mTOR inhibitor) in recurrent HGG patients, aiming to identify brain-penetrant combinations and assess their impact on malignant cell states. We enrolled 24 patients with recurrent HGG, characterized by CDKN2A/B deletion or CDK4/6 amplification, PTEN loss or PIK3CA mutations, and wildtype retinoblastoma protein (Rb). Tumors were evaluated for pharmacokinetics, pharmacodynamics, and single nucleus transcriptomics.
    RESULTS: Median unbound ribociclib concentrations in Gadolinium non-enhancing tumor regions were significantly above the biochemical IC50 for CDK4/6 inhibition at 400 and 600 mg QD doses. Unbound everolimus concentrations were undetectable (< 0.1 nM) in tumor regions across all dose levels. Ribociclib treatment was associated with significantly decreased Ki-67 positive cells. Single nucleus RNA sequencing of 17 on-trial IDH-wildtype recurrences and 88 standard-of-care treated recurrences showed a significantly lower fraction of cycling and neural progenitor-like malignant cell populations in ribociclib-everolimus treated tumors. CDK4/6 inhibitor-directed malignant cell state shifts were validated using three patient-derived cell lines.
    CONCLUSIONS: This trial underscores the value of integrating pharmacokinetics, pharmacodynamics, and single nucleus transcriptomics in Phase 0/1 surgical studies to assess treatment effects, including malignant cell state shifts. ClinicalTrials.gov identifier: NCT03834740.
    Keywords:  CDK4; glioma; ribociclib; single cell; targeted therapy
    DOI:  https://doi.org/10.1093/neuonc/noaf257
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