bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2022–12–04
seven papers selected by
Oltea Sampetrean, Keio University
  1. Neuronal and tumourigenic boundaries of glioblastoma plasticity.
  2. Glioma stem cells activate platelets by plasma-independent thrombin production to promote glioblastoma tumorigenesis.
  3. Trotabresib, an oral potent bromodomain and extraterminal inhibitor, in patients with high-grade gliomas: a phase I, "windowofopportunity" study.
  4. Real-time drug testing of paediatric diffuse midline glioma to support clinical decision making: The Zurich DIPG/DMG centre experience.
  5. Epigenetic Rewiring Underlies SMARCA4-Dependent Maintenance of Progenitor State in Pediatric H3K27M Diffuse Midline Glioma.
  6. Cerebrospinal fluid methylome-based liquid biopsies for accurate malignant brain neoplasm classification.
  7. Commentary on "Dysfunctional dendritic cells limit antigen-specific T cell response in glioma."
  1. Trends Cancer. 2022 Nov 14. pii: S2405-8033(22)00233-3. [Epub ahead of print]
    Neuronal and tumourigenic boundaries of glioblastoma plasticity.
    Manam Inushi De Silva, Brett W Stringer, Cedric Bardy.
      Glioblastoma (GBM) remains the most lethal primary brain cancer largely due to recurrence of treatment-resistant disease. Current therapies are ultimately ineffective as GBM tumour cells adapt their identity to escape treatment. Recent advances in single-cell epigenetics and transcriptomics highlight heterogeneous cell populations in GBM tumours originating from unique cancerous genetic aberrations. However, they also suggest that tumour cells conserve molecular properties of parent neuronal cells, with their permissive epigenetic profiles enabling them to morph along a finite number of reprogramming routes to evade treatment. Here, we review the known tumourigenic, neurodevelopmental and brain-injury boundaries of GBM plasticity, and propose that effective treatment of GBM requires the addition of therapeutics that restrain GBM plasticity.
    Keywords:  brain cancer; cellular reprogramming; epigenetics; genetics; glioma; neurodevelopment; stem cells; transcriptomics; treatment-resistance; tumour plasticity
    DOI:  https://doi.org/10.1016/j.trecan.2022.10.010
  2. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac172
    Glioma stem cells activate platelets by plasma-independent thrombin production to promote glioblastoma tumorigenesis.
    Anthony R Sloan, Christine Lee-Poturalski, Harry C Hoffman, Peggy L Harris, Theresa E Elder, Brian Richardson, Amber Kerstetter-Fogle, Gino Cioffi, Julia Schroer, Ansh Desai, Mark Cameron, Jill Barnholtz-Sloan, Jeremy Rich, Eckhard Jankowsky, Anirban Sen Gupta, Andrew E Sloan.
       Background: The interaction between platelets and cancer cells has been underexplored in solid tumor models that do not metastasize, for example, glioblastoma (GBM) where metastasis is rare. Histologically, it is known that glioma stem cells (GSCs) are found in perivascular and pseudsopalisading regions of GBM, which are also areas of platelet localization. High platelet counts have been associated with poor clinical outcomes in many cancers. While platelets are known to promote the progression of other tumors, mechanisms by which platelets influence GBM oncogenesis are unknown. Here, we aimed to understand how the bidirectional interaction between platelets and GSCs drives GBM oncogenesis.
    Methods: Male and female NSG mice were transplanted with GSC lines and treated with antiplatelet and anti-thrombin inhibitors. Immunofluorescence, qPCR, and Western blots were used to determine expression of coagulation mechanism in GBM tissue and subsequent GSC lines.
    Results: We show that GSCs activate platelets by endogenous production of all the factors of the intrinsic and extrinsic coagulation cascades in a plasma-independent manner. Therefore, GSCs produce thrombin resulting in platelet activation. We further demonstrate that the endogenous coagulation cascades of these cancer stem cells are tumorigenic: they activate platelets to promote stemness and proliferation in vitro and pharmacological inhibition delays tumor growth in vivo.
    Conclusions: Our findings uncover a specific preferential relationship between platelets and GSCs that drive GBM malignancies and identify a therapeutically targetable novel interaction.
    Keywords:  coagulation; glioma stem cells; thrombin
    DOI:  https://doi.org/10.1093/noajnl/vdac172
  3. Neuro Oncol. 2022 Dec 01. pii: noac263. [Epub ahead of print]
    Trotabresib, an oral potent bromodomain and extraterminal inhibitor, in patients with high-grade gliomas: a phase I, "windowofopportunity" study.
    Victor Moreno, Juan Manuel Sepulveda, David A Reardon, Ángel Pérez-Núñez, Pedro González León, Bishoy Hanna, Ellen Filvaroff, Ida Aronchik, Henry Chang, Barbara Amoroso, Marlene Zuraek, Tania Sanchez-Perez, Cristina Mendez, Daniel Stephens, Zariana Nikolova, Michael A Vogelbaum.
       BACKGROUND: The bromodomain and extraterminal protein (BET) inhibitor trotabresib has demonstrated antitumor activity in patients with advanced solid tumors, including high-grade gliomas. CC-90010-GBM-001 (NCT04047303) is a phase I study investigating the pharmacokinetics, pharmacodynamics, and CNS penetration of trotabresib in patients with recurrent high-grade gliomas scheduled for salvage resection.
    METHODS: Patients received trotabresib 30 mg/day on days 1-4 before surgery, followed by maintenance trotabresib 45 mg/day 4 days on/24 days off after surgery. Primary endpoints were plasma pharmacokinetics and trotabresib concentrations in resected tissue. Secondary and exploratory endpoints included safety, pharmacodynamics, and antitumor activity.
    RESULTS: Twenty patients received preoperative trotabresib and underwent resection with no delays or cancellations of surgery; 16 patients received maintenance trotabresib after recovery from surgery. Trotabresib plasma pharmacokinetics were consistent with previous data. Mean trotabresib brain tumor tissue:plasma ratio was 0.84 (estimated unbound partition coefficient [KPUU] 0.37), and modulation of pharmacodynamic markers was observed in blood and brain tumor tissue. Trotabresib was well tolerated; the most frequent grade 3/4 treatment-related adverse event during maintenance treatment was thrombocytopenia (5/16 patients). Sixmonth progression-free survival was 12%. Two patients remain on treatment with stable disease at cycles 25 and 30.
    CONCLUSIONS: Trotabresib penetrates the blood-brain-tumor barrier in patients with recurrent high-grade glioma and demonstrates target engagement in resected tumor tissue. Plasma pharmacokinetics, blood pharmacodynamics, and safety were comparable with previous results for trotabresib in patients with advanced solid tumors. Investigation of adjuvant trotabresib + temozolomide and concomitant trotabresib + temozolomide + radiotherapy in patients with newly diagnosed glioblastoma is ongoing (NCT04324840).
    Keywords:  Trotabresib; blood–brain-tumor barrier; glioblastoma; pharmacodynamics; pharmacokinetics
    DOI:  https://doi.org/10.1093/neuonc/noac263
  4. Eur J Cancer. 2022 Oct 26. pii: S0959-8049(22)01309-0. [Epub ahead of print]178 171-179
    Real-time drug testing of paediatric diffuse midline glioma to support clinical decision making: The Zurich DIPG/DMG centre experience.
    Timothy Mueller, Sandra Laternser, Ana S Guerreiro Stücklin, Nicolas U Gerber, Sulayman Mourabit, Marion Rizo, Elisabeth J Rushing, Raimund Kottke, Michael Grotzer, Niklaus Krayenbühl, Javad Nazarian, Sabine Mueller.
       BACKGROUND: Children diagnosed with diffuse midline gliomas (DMG) have an extremely poor overall survival: 9-12 months from diagnosis with currently no curative treatment options. Given DMG molecular heterogeneity, surgical biopsies are needed for molecular profiling and as part of enrolment into molecular-based and precision medicine type clinical interventions. In this study, we describe the results of real time profiling and drug testing at the diffuse intrinsic pontine glioma/DMG Research Centre at University Children's Hospital Zurich.
    METHOD: Biopsies were taken using a frame based stereotactic robot system (NeuroMate®, Renishaw) at University Children's Hospital Zurich. Tissue samples were evaluated to confirm diagnosis by H3K27M and H3K27 trimethylation loss. Genomic analyses were done using a variety of platforms (INFORM, Oncomine, UCSF500 gene panel). Cell lines were developed by mechanical tissue dissociation and verified by either sequencing or immunofluorescence staining confirming H3K27M mutation and used afterwards for drug testing.
    RESULTS: Twenty-five robot-assisted primary biopsies were successfully performed. Median hospital stay was 2 days (range 1-4 days). Nine low-passage patient-derived cells were developed, whereas 8 cell lines were used to inform response to clinically relevant drugs. Genome and RNA expression were used to further guide treatment strategies with targeted agents such as dual PI3K/mTOR inhibitor paxalisib.
    CONCLUSION: We established a systematic workflow for safe, robot-assisted brainstem biopsies and in-house tissue processing, followed by real-time drug testing. This provides valuable insights into tumour prognostic and individual treatment strategies targeting relevant vulnerabilities in these tumours in a clinically meaningful time frame.
    Keywords:  Brainstem biopsy; Diffuse intrinsic pontine glioma; Diffuse midline glioma; Neurosurgery; Paediatric brain cancer; Patient derived cell lines; Preclinical; Targeted therapy; Translational
    DOI:  https://doi.org/10.1016/j.ejca.2022.10.014
  5. Cancer Discov. 2022 Dec 02. 12(12): 2730-2732
    Epigenetic Rewiring Underlies SMARCA4-Dependent Maintenance of Progenitor State in Pediatric H3K27M Diffuse Midline Glioma.
    Mary Clare Beytagh, William A Weiss.
      Epigenetic reprogramming drives tumorigenesis in pediatric H3K27M diffuse midline glioma (DMG) by altering the canonical functions of chromatin remodeling complexes. These studies (i) identified BRG1 (encoded by SMARCA4), the catalytic subunit of the mammalian SWI/SNF (BAF) chromatin remodeling complex, as a novel dependency in pediatric H3K27M glioma; (ii) investigated the molecular mechanisms underlying the maintenance of the progenitor state; and (iii) demonstrated efficacy for BRG1 inhibitors.The authors identified the BRG1 ATPase as a dependency in pediatric H3K27M-mutant DMG. SOX10 recruits BRG1 to regulatory elements to drive progression. Pharmacologically targeting BRG1 reduced tumor volume and improved survival in vivo. Inhibiting BRG1 ATPase represents a potential therapeutic strategy for pediatric H3K27M DMG. See related article by Panditharatna et al., p. 2880 (5) See related article by Mo et al., p. 2906 (4) .
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-1030
  6. Neuro Oncol. 2022 Dec 01. pii: noac264. [Epub ahead of print]
    Cerebrospinal fluid methylome-based liquid biopsies for accurate malignant brain neoplasm classification.
    Jeffrey A Zuccato, Vikas Patil, Sheila Mansouri, Mathew Voisin, Ankur Chakravarthy, Shu Yi Shen, Farshad Nassiri, Nicholas Mikolajewicz, Mara Trifoi, Anna Skakodub, Brad Zacharia, Michael Glantz, Daniel D De Carvalho, Alireza Mansouri, Gelareh Zadeh.
       BACKGROUND: Resolving the differential diagnosis between brain metastases (BM), glioblastomas (GBM), and central nervous system lymphomas (CNSL) is an important dilemma for the clinical management of the main three intra-axial brain tumor types. Currently, treatment decisions require invasive diagnostic surgical biopsies that carry risks and morbidity. This study aimed to utilize methylomes from cerebrospinal fluid (CSF), a biofluid proximal to brain tumors, for reliable non-invasive classification that addresses limitations associated with low target abundance in existing approaches.
    METHODS: Binomial GLMnet classifiers of tumor type were built, in fifty iterations of 80% discovery sets, using CSF methylomes obtained from 57 BM, GBM, CNSL, and non-neoplastic control patients. Publicly-available tissue methylation profiles (N=197) on these entities and normal brain parenchyma were used for validation and model optimization.
    RESULTS: Models reliably distinguished between BM (area under receiver operating characteristic curve [AUROC]=0.93, 95% confidence interval [CI]: 0.71-1.0), GBM (AUROC=0.83, 95% CI: 0.63-1.0), and CNSL (AUROC=0.91, 95% CI: 0.66-1.0) in independent 20% validation sets. For validation, CSF-based methylome signatures reliably distinguished between tumor types within external tissue samples and tumors from non-neoplastic controls in CSF and tissue. CSF methylome signals were observed to align closely with tissue signatures for each entity. An additional set of optimized CSF-based models, built using tumor-specific features present in tissue data, showed enhanced classification accuracy.
    CONCLUSIONS: CSF methylomes are reliable for liquid biopsy-based classification of the major three malignant brain tumor types. We discuss how liquid biopsies may impact brain cancer management in the future by avoiding surgical risks, classifying unbiopsiable tumors, and guiding surgical planning when resection is indicated.
    Keywords:  Brain cancer; DNA methylation; cerebrospinal fluid; diagnostic biomarkers; liquid biopsy
    DOI:  https://doi.org/10.1093/neuonc/noac264
  7. Neuro Oncol. 2022 Nov 29. pii: noac256. [Epub ahead of print]
    Commentary on "Dysfunctional dendritic cells limit antigen-specific T cell response in glioma."
    Robert M Prins, Richard G Everson.
      
    DOI:  https://doi.org/10.1093/neuonc/noac256
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