bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2024–02–25
six papers selected by
Oltea Sampetrean, Keio University
  1. Selective DRD2 Antagonist and ClpP Agonist ONC201 in a Recurrent Non-midline H3 K27M-mutant Glioma Cohort.
  2. Dysregulated inter-mitochondrial crosstalk in glioblastoma cells revealed by in situ cryo-electron tomography.
  3. Cancer stem cell hypothesis 2.0 in glioblastoma: Where are we now and where are we going?
  4. Enhancing CAR-T cell metabolism to overcome hypoxic conditions in the brain tumor microenvironment.
  5. Therapeutic Strategies for Gliomas Associated With Cancer Predisposition Syndromes.
  6. Repeated blood-brain barrier opening with a nine-emitter implantable ultrasound device in combination with carboplatin in recurrent glioblastoma: a phase I/II clinical trial.
  1. Neuro Oncol. 2024 Feb 22. pii: noae021. [Epub ahead of print]
    Selective DRD2 Antagonist and ClpP Agonist ONC201 in a Recurrent Non-midline H3 K27M-mutant Glioma Cohort.
    Yazmin Odia, Matthew D Hall, Timothy Francis Cloughesy, Patrick Y Wen, Isabel Arrillaga-Romany, Doured Daghistani, Minesh P Mehta, Rohinton S Tarapore, Samuel C Ramage, Joshua E Allen.
       BACKGROUND: Diffuse midline glioma, H3 K27-altered (H3 K27M-altered DMG) are invariably lethal, disproportionately affecting the young and without effective treatment besides radiotherapy. The 2016 WHO CNS Tumors Classification defined H3K27M mutations as pathognomonic but restricted diagnosis to diffuse gliomas involving midline structures by 2018. Dordaviprone (ONC201) is an oral investigational small molecule, DRD2 antagonist and ClpP agonist associated with durable responses in recurrent H3K27M-mutant DMG. Activity of ONC201 in non-midline H3K27M-mutant diffuse gliomas has not been reported.
    METHODS: Patients with recurrent non-midline H3K27M-mutant diffuse gliomas treated with ONC201 were enrolled on 5 trials. Eligibility included measurable disease by Response Assessment in Neuro-Oncology (RANO) high-grade glioma (HGG), Karnofsky/Lansky performance score (KPS/LPS) ≥60, and ≥90 days from radiation. The primary endpoint was overall response rate (ORR).
    RESULTS: Five patients with cerebral gliomas (3 frontal, 1 temporal, and 1 parietal) met inclusion. One complete and one partial response were reported by investigators. Blinded independent central review confirmed ORR by RANO criteria for two, however one deemed nonmeasurable and another stable. A responding patient also noted improved mobility and alertness.
    CONCLUSIONS: H3K27M-mutant diffuse gliomas occasionally occur in nonmidline cerebrum. ONC201 exhibits activity in H3K27M-mutant gliomas irrespective of CNS location.
    Keywords:  ClpP; DRD2; H3 K27M-mutant Glioma; Non-midline H3K27M-mutant Glioma; ONC201
    DOI:  https://doi.org/10.1093/neuonc/noae021
  2. Proc Natl Acad Sci U S A. 2024 Feb 27. 121(9): e2311160121
    Dysregulated inter-mitochondrial crosstalk in glioblastoma cells revealed by in situ cryo-electron tomography.
    Rui Wang, Huan Lei, Hongxiang Wang, Lei Qi, Yu'e Liu, Yunhui Liu, Yufeng Shi, Juxiang Chen, Qing-Tao Shen.
      Glioblastomas (GBMs) are the most lethal primary brain tumors with limited survival, even under aggressive treatments. The current therapeutics for GBMs are flawed due to the failure to accurately discriminate between normal proliferating cells and distinctive tumor cells. Mitochondria are essential to GBMs and serve as potential therapeutical targets. Here, we utilize cryo-electron tomography to quantitatively investigate nanoscale details of randomly sampled mitochondria in their native cellular context of GBM cells. Our results show that compared with cancer-free brain cells, GBM cells own more inter-mitochondrial junctions of several types for communications. Furthermore, our tomograms unveil microtubule-dependent mitochondrial nanotunnel-like bridges in the GBM cells as another inter-mitochondrial structure. These quantified inter-mitochondrial features, together with other mitochondria-organelle and intra-mitochondrial ones, are sufficient to distinguish GBM cells from cancer-free brain cells under scrutiny with predictive modeling. Our findings decipher high-resolution inter-mitochondrial structural signatures and provide clues for diagnosis and therapeutic interventions for GBM and other mitochondria-related diseases.
    Keywords:  cryo-electron tomography; glioblastoma; mitochondria; organelle crosstalk
    DOI:  https://doi.org/10.1073/pnas.2311160121
  3. Neuro Oncol. 2024 Feb 23. pii: noae011. [Epub ahead of print]
    Cancer stem cell hypothesis 2.0 in glioblastoma: Where are we now and where are we going?
    Anthony R Sloan, Daniel J Silver, Sam Kint, Marco Gallo, Justin D Lathia.
      Over the past 2 decades, the cancer stem cell (CSC) hypothesis has provided insight into many malignant tumors, including glioblastoma (GBM). Cancer stem cells have been identified in patient-derived tumors and in some mouse models, allowing for a deeper understanding of cellular and molecular mechanisms underlying GBM growth and therapeutic resistance. The CSC hypothesis has been the cornerstone of cellular heterogeneity, providing a conceptual and technical framework to explain this longstanding phenotype in GBM. This hypothesis has evolved to fit recent insights into how cellular plasticity drives tumor growth to suggest that CSCs do not represent a distinct population but rather a cellular state with substantial plasticity that can be achieved by non-CSCs under specific conditions. This has further been reinforced by advances in genomics, including single-cell approaches, that have used the CSC hypothesis to identify multiple putative CSC states with unique properties, including specific developmental and metabolic programs. In this review, we provide a historical perspective on the CSC hypothesis and its recent evolution, with a focus on key functional phenotypes, and provide an update on the definition for its use in future genomic studies.
    Keywords:  cancer stem cell; glioblastoma; heterogeneity; proliferation
    DOI:  https://doi.org/10.1093/neuonc/noae011
  4. JCI Insight. 2024 Feb 22. pii: e177141. [Epub ahead of print]
    Enhancing CAR-T cell metabolism to overcome hypoxic conditions in the brain tumor microenvironment.
    Ryusuke Hatae, Keith Kyewalabye, Akane Yamamichi, Tiffany Chen, Su Phyu, Pavlina Chuntova, Takahide Nejo, Lauren S Levine, Matthew H Spitzer, Hideho Okada.
      The efficacy of chimeric antigen receptor (CAR)-T therapy has been limited against brain tumors to date. CAR-T cells infiltrating syngeneic intracerebral SB28-EGFRvIII glioma revealed impaired mitochondrial ATP production and a markedly hypoxic status compared to ones migrating to subcutaneous tumors. Drug screenings to improve metabolic states of T cells under hypoxic conditions led us to evaluate the combination of AMPK activator Metformin and the mTOR inhibitor Rapamycin (Met+Rap). Met+Rap-pretreated mouse CAR-T cells showed activated PPAR-gamma coactivator 1α (PGC-1α) through mTOR inhibition and AMPK activation, and a higher level of mitochondrial spare respiratory capacity than those pretreated with individual drugs or without pretreatment. Moreover, Met+Rap-pretreated CAR-T cells demonstrated persistent and effective anti-glioma cytotoxic activities in the hypoxic condition. Furthermore, a single intravenous infusion of Met+Rap-pretreated CAR-T cells significantly extended the survival of mice bearing intracerebral SB28-EGFRvIII gliomas. Mass cytometric analyses highlighted increased glioma-infiltrating CAR-T cells in the Met+Rap group with fewer Ly6c+ CD11b+ monocytic myeloid-derived suppressor cells in the tumors. Finally, human CAR-T cells pretreated with Met+Rap recapitulated the observations with murine CAR-T cells, demonstrating improved functions in vitro hypoxic conditions. These findings advocate for translational and clinical exploration of Met+Rap-pretreated CAR-T cells in human trials.
    Keywords:  Brain cancer; Cancer immunotherapy; Hypoxia; Immunology; Otology
    DOI:  https://doi.org/10.1172/jci.insight.177141
  5. JCO Precis Oncol. 2024 Feb;8 e2300442
    Therapeutic Strategies for Gliomas Associated With Cancer Predisposition Syndromes.
    Keng Lam, Carlos Kamiya-Matsuoka, John M Slopis, Ian E McCutcheon, Nazanin K Majd.
       PURPOSE: The purpose of this article was to provide an overview of syndromic gliomas.
    DESIGN: The authors conducted a nonsystematic literature review.
    RESULTS: Cancer predisposition syndromes (CPSs) are genetic conditions that increase one's risk for certain types of cancer compared with the general population. Syndromes that can predispose one to developing gliomas include neurofibromatosis, Li-Fraumeni syndrome, Lynch syndrome, and tuberous sclerosis complex. The standard treatment for sporadic glioma may involve resection, radiation therapy, and/or alkylating chemotherapy. However, DNA-damaging approaches, such as radiation and alkylating agents, may increase the risk of secondary malignancies and other complications in patients with CPSs. In some cases, depending on genetic aberrations, targeted therapies or immunotherapeutic approaches may be considered. Data on clinical characteristics, therapeutic strategies, and prognosis of syndromic gliomas remain limited.
    CONCLUSION: In this review, we provide an overview of syndromic gliomas with a focus on management for patients with CPSs and the role of novel treatments that can be considered.
    DOI:  https://doi.org/10.1200/PO.23.00442
  6. Nat Commun. 2024 Feb 23. 15(1): 1650
    Repeated blood-brain barrier opening with a nine-emitter implantable ultrasound device in combination with carboplatin in recurrent glioblastoma: a phase I/II clinical trial.
    Alexandre Carpentier, Roger Stupp, Adam M Sonabend, Henry Dufour, Olivier Chinot, Bertrand Mathon, François Ducray, Jacques Guyotat, Nathalie Baize, Philippe Menei, John de Groot, Jeffrey S Weinberg, Benjamin P Liu, Eric Guemas, Carole Desseaux, Charlotte Schmitt, Guillaume Bouchoux, Michael Canney, Ahmed Idbaih.
      Here, the results of a phase 1/2 single-arm trial (NCT03744026) assessing the safety and efficacy of blood-brain barrier (BBB) disruption with an implantable ultrasound system in recurrent glioblastoma patients receiving carboplatin are reported. A nine-emitter ultrasound implant was placed at the end of tumor resection replacing the bone flap. After surgery, activation to disrupt the BBB was performed every four weeks either before or after carboplatin infusion. The primary objective of the Phase 1 was to evaluate the safety of escalating numbers of ultrasound emitters using a standard 3 + 3 dose escalation. The primary objective of the Phase 2 was to evaluate the efficacy of BBB opening using magnetic resonance imaging (MRI). The secondary objectives included safety and clinical efficacy. Thirty-three patients received a total of 90 monthly sonications with carboplatin administration and up to nine emitters activated without observed DLT. Grade 3 procedure-related adverse events consisted of pre syncope (n = 3), fatigue (n = 1), wound infection (n = 2), and pain at time of device connection (n = 7). BBB opening endpoint was met with 90% of emitters showing BBB disruption on MRI after sonication. In the 12 patients who received carboplatin just prior to sonication, the progression-free survival was 3.1 months, the 1-year overall survival rate was 58% and median overall survival was 14.0 months from surgery.
    DOI:  https://doi.org/10.1038/s41467-024-45818-7
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