bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2024–02–11
thirteen papers selected by
Oltea Sampetrean, Keio University
  1. TREM2 mediates phagocytosis in glioblastoma.
  2. Invasion of glioma cells through confined space requires membrane tension regulation and mechano-electrical coupling via Plexin-B2.
  3. Integrated Proteogenomics Uncover Mechanisms of Glioblastoma Evolution, Pointing to Novel Therapeutic Targets.
  4. Increased interaction between connexin43 and microtubules is critical for glioblastoma stem-like cell maintenance and tumorigenicity.
  5. A clinically applicable connectivity signature for glioblastoma includes the tumor network driver CHI3L1.
  6. Redox-responsive polymer micelles co-encapsulating immune checkpoint inhibitors and chemotherapeutic agents for glioblastoma therapy.
  7. Phase 1 trial of TPI 287, a microtubule stabilizing agent, in combination with bevacizumab in adults with recurrent glioblastoma.
  8. BTF3L4 enhances malignant phenotypes through modulating tumor cell function and immune microenvironment in glioma.
  9. ONC201 (Dordaviprone) in Recurrent H3 K27M-Mutant Diffuse Midline Glioma.
  10. PI3K/mTOR is a therapeutically targetable genetic dependency in diffuse intrinsic pontine glioma.
  11. IDHwt glioblastomas can be stratified by their transcriptional response to standard treatment, with implications for targeted therapy.
  12. Gliomas: a reflection of temporal gliogenic principles.
  13. The greatest challenge for pediatric low-grade glioma.
  1. Nat Rev Neurol. 2024 Feb 07.
    TREM2 mediates phagocytosis in glioblastoma.
    Lisa Kiani.
      
    DOI:  https://doi.org/10.1038/s41582-024-00935-1
  2. bioRxiv. 2024 Jan 02. pii: 2024.01.02.573660. [Epub ahead of print]
    Invasion of glioma cells through confined space requires membrane tension regulation and mechano-electrical coupling via Plexin-B2.
    Chrystian Junqueira Alves, Theodore Hannah, Sita Sadia, Christy Kolsteeg, Angela Dixon, Robert J Wiener, Ha Nguyen, Murray J Tipping, Júlia Silva Ladeira, Paula Fernandes da Costa Franklin, Nathália de Paula Dutra de Nigro, Rodrigo Alves Dias, Priscila V Zabala Capriles, José P Rodrigues Furtado de Mendonça, Paul Slesinger, Kevin Costa, Hongyan Zou, Roland H Friedel.
      Glioblastoma (GBM) is a malignant brain tumor with uncontrolled invasive growth. Here, we demonstrate how GBM cells usurp guidance receptor Plexin-B2 to gain biomechanical plasticity for polarized migration through confined space. Using live-cell imaging to track GBM cells negotiating microchannels, we reveal active endocytosis at cell front and filamentous actin assembly at rear to propel GBM cells through constrictions. These two processes are interconnected and governed by Plexin-B2 that orchestrates cortical actin and membrane tension, shown by biomechanical assays. Molecular dynamics simulations predict that balanced membrane and actin tension are required for optimal migratory velocity and consistency. Furthermore, Plexin-B2 mechanosensitive function requires a bendable extracellular ring structure and affects membrane internalization, permeability, phospholipid composition, as well as inner membrane surface charge. Together, our studies unveil a key element of membrane tension and mechanoelectrical coupling via Plexin-B2 that enables GBM cells to adapt to physical constraints and achieve polarized confined migration.
    DOI:  https://doi.org/10.1101/2024.01.02.573660
  3. Cancer Res. 2024 Feb 08.
    Integrated Proteogenomics Uncover Mechanisms of Glioblastoma Evolution, Pointing to Novel Therapeutic Targets.
    Jiabo Li, Ling-Kai Shih, Daniel J Brat.
      Nearly all glioblastoma (GBM) patients relapse following standard treatment and eventually succumb to disease. While large scale, integrated multi-omic studies have tremendously advanced the understanding of primary GBM at the cellular and molecular level, the post-therapeutic trajectory and biological properties of recurrent GBM remain poorly understood. This knowledge gap was addressed in a recent Cancer Cell article in which Kim and colleagues report on a highly integrative proteogenomic analysis performed on 123 matched primary and recurrent GBMs that uncovered a dramatic evolutionary shift from a proliferative state at initial diagnosis to the activation of neuronal and synaptogenic pathways at recurrence following therapy. Neuronal transition was characterized by post-translational activation of WNT/PCP signaling and BRAF kinase, while many canonical oncogenic pathways, and EGFR in particular, were downregulated. Parallel multi-omics analyses of patient-derived xenograft (PDX) models corroborated this evolutionary trajectory, allowing in vivo experiments for translational significance. Notably, targeting BRAF kinase disrupted both the neuronal transition and migration capabilities of recurrent gliomas, which were key characteristics of post-treatment progression. Furthermore, combining BRAF inhibitor vemurafenib with temozolomide (TMZ) prolonged survival in PDX models. Overall, the results reveal novel biological mechanisms of GBM evolution and therapy resistance, and suggest promising therapeutic intervention.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-0452
  4. bioRxiv. 2024 Jan 27. pii: 2024.01.26.576347. [Epub ahead of print]
    Increased interaction between connexin43 and microtubules is critical for glioblastoma stem-like cell maintenance and tumorigenicity.
    James W Smyth, Sujuan Guo, Lorie O'Rourke, Stacie Deaver, Jacob Dahlka, Elmar Nurmemmedov, Zhi Sheng, Robert G Gourdie, Samy Lamouille.
      Glioblastoma (GBM) is the most common primary tumor of the central nervous system. One major challenge in GBM treatment is the resistance to chemotherapy and radiotherapy observed in subpopulations of cancer cells, including GBM stem-like cells (GSCs). These cells hold the ability to self-renew or differentiate following treatment, participating in tumor recurrence. The gap junction protein connexin43 (Cx43) has complex roles in oncogenesis and we have previously demonstrated an association between Cx43 and GBM chemotherapy resistance. Here, we report, for the first time, increased direct interaction between non-junctional Cx43 with microtubules in the cytoplasm of GSCs. We hypothesize that non-junctional Cx43/microtubule complexing is critical for GSC maintenance and survival and sought to specifically disrupt this interaction while maintaining other Cx43 functions, such as gap junction formation. Using a Cx43 mimetic peptide of the carboxyl terminal tubulin-binding domain of Cx43 (JM2), we successfully ablated Cx43 interaction with microtubules in GSCs. Importantly, administration of JM2 significantly decreased GSC survival in vitro , and limited GSC-derived tumor growth in vivo . Together, these results identify JM2 as a novel peptide drug to ablate GSCs in GBM treatment.
    DOI:  https://doi.org/10.1101/2024.01.26.576347
  5. Nat Commun. 2024 Feb 06. 15(1): 968
    A clinically applicable connectivity signature for glioblastoma includes the tumor network driver CHI3L1.
    Ling Hai, Dirk C Hoffmann, Robin J Wagener, Daniel D Azorin, David Hausmann, Ruifan Xie, Magnus-Carsten Huppertz, Julien Hiblot, Philipp Sievers, Sophie Heuer, Jakob Ito, Gina Cebulla, Alexandros Kourtesakis, Leon D Kaulen, Miriam Ratliff, Henriette Mandelbaum, Erik Jung, Ammar Jabali, Sandra Horschitz, Kati J Ernst, Denise Reibold, Uwe Warnken, Varun Venkataramani, Rainer Will, Mario L Suvà, Christel Herold-Mende, Felix Sahm, Frank Winkler, Matthias Schlesner, Wolfgang Wick, Tobias Kessler.
      Tumor microtubes (TMs) connect glioma cells to a network with considerable relevance for tumor progression and therapy resistance. However, the determination of TM-interconnectivity in individual tumors is challenging and the impact on patient survival unresolved. Here, we establish a connectivity signature from single-cell RNA-sequenced (scRNA-Seq) xenografted primary glioblastoma (GB) cells using a dye uptake methodology, and validate it with recording of cellular calcium epochs and clinical correlations. Astrocyte-like and mesenchymal-like GB cells have the highest connectivity signature scores in scRNA-sequenced patient-derived xenografts and patient samples. In large GB cohorts, TM-network connectivity correlates with the mesenchymal subtype and dismal patient survival. CHI3L1 gene expression serves as a robust molecular marker of connectivity and functionally influences TM networks. The connectivity signature allows insights into brain tumor biology, provides a proof-of-principle that tumor cell TM-connectivity is relevant for patients' prognosis, and serves as a robust prognostic biomarker.
    DOI:  https://doi.org/10.1038/s41467-024-45067-8
  6. Nat Commun. 2024 Feb 06. 15(1): 1118
    Redox-responsive polymer micelles co-encapsulating immune checkpoint inhibitors and chemotherapeutic agents for glioblastoma therapy.
    Zhiqi Zhang, Xiaoxuan Xu, Jiawei Du, Xin Chen, Yonger Xue, Jianqiong Zhang, Xue Yang, Xiaoyuan Chen, Jinbing Xie, Shenghong Ju.
      Immunotherapy with immune checkpoint blockade (ICB) for glioblastoma (GBM) is promising but its clinical efficacy is seriously challenged by the blood-tumor barrier (BTB) and immunosuppressive tumor microenvironment. Here, anti-programmed death-ligand 1 antibodies (aPD-L1) are loaded into a redox-responsive micelle and the ICB efficacy is further amplified by paclitaxel (PTX)-induced immunogenic cell death (ICD) via a co-encapsulation approach for the reinvigoration of local anti-GBM immune responses. Consequently, the micelles cross the BTB and are retained in the reductive tumor microenvironment without altering the bioactivity of aPD-L1. The ICB efficacy is enhanced by the aPD-L1 and PTX combination with suppression of primary and recurrent GBM, accumulation of cytotoxic T lymphocytes, and induction of long-lasting immunological memory in the orthotopic GBM-bearing mice. The co-encapsulation approach facilitating efficient antibody delivery and combining with chemotherapeutic agent-induced ICD demonstrate that the chemo-immunotherapy might reprogram local immunity to empower immunotherapy against GBM.
    DOI:  https://doi.org/10.1038/s41467-024-44963-3
  7. Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdae009
    Phase 1 trial of TPI 287, a microtubule stabilizing agent, in combination with bevacizumab in adults with recurrent glioblastoma.
    Samuel A Goldlust, Louis B Nabors, Sigmund Hsu, Nimish Mohile, Paul J Duic, Tara Benkers, Samuel Singer, Mayank Rao, Lori Cappello, Sandra L Silberman, George Farmer.
       Background: Recurrent glioblastoma (rGBM) has limited treatment options. This phase 1 protocol was designed to study the safety and preliminary efficacy of TPI 287, a central nervous system penetrant microtubule stabilizer, in combination with bevacizumab (BEV) for the treatment of rGBM.
    Methods: GBM patients with up to 2 prior relapses without prior exposure to anti-angiogenic therapy were eligible. A standard 3 + 3 design was utilized to determine the maximum tolerated dose (MTD) of TPI 287. Cohorts received TPI 287 at 140-220 mg/m2 every 3 weeks and BEV 10 mg/kg every 2 weeks during 6-week cycles. An MRI was performed after each cycle, and treatment continued until progression as determined via response assessment in neuro-oncology criteria.
    Results: Twenty-four patients were enrolled at 6 centers. Treatment was generally well tolerated. Fatigue, myelosuppression, and peripheral neuropathy were the most common treatment emergent adverse events. Dose-limiting toxicity was not observed, thus the MTD was not determined. Twenty-three patients were evaluable for median and 6-month progression-free survival, which were 5.5 months (mo) and 40%, respectively. Median and 12-month overall survival were 13.4 mo and 64%, respectively. The optimal phase 2 dose was determined to be 200 mg/m2.
    Conclusions: TPI 287 can be safely combined with BEV for the treatment of rGBM and preliminary efficacy supports further investigation of this combination.
    Keywords:  bevacizumab; clinical trial; glioblastoma; phase 1; taxane
    DOI:  https://doi.org/10.1093/noajnl/vdae009
  8. Am J Pathol. 2024 Feb 04. pii: S0002-9440(24)00042-7. [Epub ahead of print]
    BTF3L4 enhances malignant phenotypes through modulating tumor cell function and immune microenvironment in glioma.
    Bing Lu, Tianyi Lu, Jiawen Shi, Pingping Sun, Xiaojng Zhang, Lei Yang, Ziheng Wang, Jianfei Huang.
      Recent investigations into the tumor microenvironment have provided insights into the limited response of glioma progression to immunotherapy. However, the specific involvement of Basic Transcription Factor 3 Like 4 (BTF3L4) in glioma progression and its correlation with immune cell infiltration remained areas of uncertainty that require further exploration. In the present study, BTF3L4 expression was delineated using gene-expression-profiling-interactive-analysis and multiplex-immunohistological staining of tissue microarrays. Then, the prognostic value of BTF3L4 was assessed using Cox regression models and Kaplan-Meier methods and conducted in vitro experiments to investigate how BTF3L4 protein impacts the proliferation, migration, and invasion capabilities of glioma cells. Furthermore, the Cibersort and Estimate methods were employed to quantify immune cells that correlate to BTF3L4 expression and applied multiplex-immunohistological staining to investigate its correlation with infiltrated immune cells in glioma tissues. These findings revealed a higher BTF3L4 expression in glioma tissues compared to non-tumor brain tissues, which correlated with clinical characteristics and worse patient prognosis. Furthermore, the downregulation of BTF3L4 protein in glioma cell line had a detrimental effect on cell migration, invasion, and proliferation. Additionally, the association between BTF3L4 and key immune molecules in glioma, particularly with the infiltration of CD66B+ neutrophils and PD-L1 expression was identified. These results highlight the prognostic significance of BTF3L4 and propose BTF3L4 as a potential target for glioma immune therapy.
    Keywords:  BTF3L4; glioma; neutrophil; prognosis; tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.ajpath.2024.01.011
  9. J Clin Oncol. 2024 Feb 09. JCO2301134
    ONC201 (Dordaviprone) in Recurrent H3 K27M-Mutant Diffuse Midline Glioma.
    Isabel Arrillaga-Romany, Sharon L Gardner, Yazmin Odia, Dolly Aguilera, Joshua E Allen, Tracy Batchelor, Nicholas Butowski, Clark Chen, Timothy Cloughesy, Andrew Cluster, John de Groot, Karan S Dixit, Jerome J Graber, Aya M Haggiagi, Rebecca A Harrison, Albert Kheradpour, Lindsay Kilburn, Sylvia C Kurz, Guangrong Lu, Tobey J MacDonald, Minesh Mehta, Allen S Melemed, Phioanh Leia Nghiemphu, Samuel C Ramage, Nicole Shonka, Ashley Sumrall, Rohinton Tarapore, Lynne Taylor, Yoshie Umemura, Patrick Y Wen.
       PURPOSE: Histone 3 (H3) K27M-mutant diffuse midline glioma (DMG) has a dismal prognosis with no established effective therapy beyond radiation. This integrated analysis evaluated single-agent ONC201 (dordaviprone), a first-in-class imipridone, in recurrent H3 K27M-mutant DMG.
    METHODS: Fifty patients (pediatric, n = 4; adult, n = 46) with recurrent H3 K27M-mutant DMG who received oral ONC201 monotherapy in four clinical trials or one expanded access protocol were included. Eligible patients had measurable disease by Response Assessment in Neuro-Oncology (RANO) high-grade glioma (HGG) criteria and performance score (PS) ≥60 and were ≥90 days from radiation; pontine and spinal tumors were ineligible. The primary end point was overall response rate (ORR) by RANO-HGG criteria. Secondary end points included duration of response (DOR), time to response (TTR), corticosteroid response, PS response, and ORR by RANO low-grade glioma (LGG) criteria. Radiographic end points were assessed by dual-reader, blinded independent central review.
    RESULTS: The ORR (RANO-HGG) was 20.0% (95% CI, 10.0 to 33.7). The median TTR was 8.3 months (range, 1.9-15.9); the median DOR was 11.2 months (95% CI, 3.8 to not reached). The ORR by combined RANO-HGG/LGG criteria was 30.0% (95% CI, 17.9 to 44.6). A ≥50% corticosteroid dose reduction occurred in 7 of 15 evaluable patients (46.7% [95% CI, 21.3 to 73.4]); PS improvement occurred in 6 of 34 evaluable patients (20.6% [95% CI, 8.7 to 37.9]). Grade 3 treatment-related treatment-emergent adverse events (TR-TEAEs) occurred in 20.0% of patients; the most common was fatigue (n = 5; 10%); no grade 4 TR-TEAEs, deaths, or discontinuations occurred.
    CONCLUSION: ONC201 monotherapy was well tolerated and exhibited durable and clinically meaningful efficacy in recurrent H3 K27M-mutant DMG.
    DOI:  https://doi.org/10.1200/JCO.23.01134
  10. J Clin Invest. 2024 Feb 06. pii: e170329. [Epub ahead of print]
    PI3K/mTOR is a therapeutically targetable genetic dependency in diffuse intrinsic pontine glioma.
    Ryan J Duchatel, Evangeline R Jackson, Sarah G Parackal, Dylan Kiltschewskij, Izac J Findlay, Abdul Mannan, Dilana E Staudt, Bryce C Thomas, Zacary P Germon, Sandra Laternser, Padraic S Kearney, M Fairuz B Jamaluddin, Alicia M Douglas, Tyrone S Beitaki, Holly P McEwen, Mika L Persson, Emily A Hocke, Vaibhav Jain, Michael Aksu, Elizabeth E Manning, Heather C Murray, Nicole M Verrills, Claire Xin Sun, Paul Daniel, Ricardo E Vilain, David A Skerrett-Byrne, Brett Nixon, Susan Hua, Charles E de Bock, Yolanda Colino-Sanguino, Fatima Valdes-Mora, Maria Tsoli, David S Ziegler, Murray J Cairns, Eric H Raabe, Nicholas A Vitanza, Esther Hulleman, Timothy N Phoenix, Carl Koschmann, Frank Alvaro, Christopher V Dayas, Christopher L Tinkle, Helen Wheeler, James R Whittle, David D Eisenstat, Ron Firestein, Sabine Mueller, Santosh Valvi, Jordan R Hansford, David M Ashley, Simon G Gregory, Lindsay B Kilburn, Javad Nazarian, Jason E Cain, Matthew D Dun.
      Diffuse midline glioma (DMG), including tumors diagnosed in the brainstem (diffuse intrinsic pontine glioma - DIPG), are uniformly fatal brain tumors that lack effective treatment. Analysis of CRISPR-Cas9 loss-of-function gene deletion screens identified PIK3CA and MTOR as targetable molecular dependencies across DIPG patient models, highlighting the therapeutic potential of the blood-brain barrier penetrant PI3K/Akt/mTOR inhibitor, paxalisib. At the human equivalent maximum tolerated dose, mice treated with paxalisib experienced systemic glucose feedback and increased insulin levels commensurate with patients using PI3K inhibitors. To exploit genetic dependence and overcome resistance whilst maintaining compliance and therapeutic benefit, we combined paxalisib with the anti-hyperglycemic drug, metformin. Metformin restored glucose homeostasis and decreased phosphorylation of the insulin receptor in vivo, a common mechanism of PI3K-inhibitor resistance, extending survival of orthotopic models. DIPG models treated with paxalisib increased calcium-activated PKC signaling. The brain penetrant PKC inhibitor enzastaurin in combination with paxalisib, synergistically extended the survival of multiple orthotopic patient-derived and immunocompetent syngeneic allograft models; benefits potentiated in combination with metformin and standard-of-care radiotherapy. Therapeutic adaptation was assessed using spatial transcriptomics and ATAC-sequencing, identifying changes in myelination and tumor immune microenvironment crosstalk. Together, we have identified a clinically relevant DIPG therapeutic combinatorial approach.
    Keywords:  Brain cancer; Drug therapy; Oncogenes; Oncology; Therapeutics
    DOI:  https://doi.org/10.1172/JCI170329
  11. Genome Biol. 2024 Feb 07. 25(1): 45
    IDHwt glioblastomas can be stratified by their transcriptional response to standard treatment, with implications for targeted therapy.
    Georgette Tanner, Rhiannon Barrow, Shoaib Ajaib, Muna Al-Jabri, Nazia Ahmed, Steven Pollock, Martina Finetti, Nora Rippaus, Alexander F Bruns, Khaja Syed, James A Poulter, Laura Matthews, Thomas Hughes, Erica Wilson, Colin Johnson, Frederick S Varn, Anke Brüning-Richardson, Catherine Hogg, Alastair Droop, Arief Gusnanto, Matthew A Care, Luisa Cutillo, David R Westhead, Susan C Short, Michael D Jenkinson, Andrew Brodbelt, Aruna Chakrabarty, Azzam Ismail, Roel G W Verhaak, Lucy F Stead.
       BACKGROUND: Glioblastoma (GBM) brain tumors lacking IDH1 mutations (IDHwt) have the worst prognosis of all brain neoplasms. Patients receive surgery and chemoradiotherapy but tumors almost always fatally recur.
    RESULTS: Using RNA sequencing data from 107 pairs of pre- and post-standard treatment locally recurrent IDHwt GBM tumors, we identify two responder subtypes based on longitudinal changes in gene expression. In two thirds of patients, a specific subset of genes is upregulated from primary to recurrence (Up responders), and in one third, the same genes are downregulated (Down responders), specifically in neoplastic cells. Characterization of the responder subtypes indicates subtype-specific adaptive treatment resistance mechanisms that are associated with distinct changes in the tumor microenvironment. In Up responders, recurrent tumors are enriched in quiescent proneural GBM stem cells and differentiated neoplastic cells, with increased interaction with the surrounding normal brain and neurotransmitter signaling, whereas Down responders commonly undergo mesenchymal transition. ChIP-sequencing data from longitudinal GBM tumors suggests that the observed transcriptional reprogramming could be driven by Polycomb-based chromatin remodeling rather than DNA methylation.
    CONCLUSIONS: We show that the responder subtype is cancer-cell intrinsic, recapitulated in in vitro GBM cell models, and influenced by the presence of the tumor microenvironment. Stratifying GBM tumors by responder subtype may lead to more effective treatment.
    DOI:  https://doi.org/10.1186/s13059-024-03172-3
  12. Commun Biol. 2024 Feb 06. 7(1): 156
    Gliomas: a reflection of temporal gliogenic principles.
    Caitlin Sojka, Steven A Sloan.
      The hijacking of early developmental programs is a canonical feature of gliomas where neoplastic cells resemble neurodevelopmental lineages and possess mechanisms of stem cell resilience. Given these parallels, uncovering how and when in developmental time gliomagenesis intersects with normal trajectories can greatly inform our understanding of tumor biology. Here, we review how elapsing time impacts the developmental principles of astrocyte (AS) and oligodendrocyte (OL) lineages, and how these same temporal programs are replicated, distorted, or circumvented in pathological settings such as gliomas. Additionally, we discuss how normal gliogenic processes can inform our understanding of the temporal progression of gliomagenesis, including when in developmental time gliomas originate, thrive, and can be pushed towards upon therapeutic coercion.
    DOI:  https://doi.org/10.1038/s42003-024-05833-2
  13. Neuro Oncol. 2024 Feb 10. pii: noae004. [Epub ahead of print]
    The greatest challenge for pediatric low-grade glioma.
    Daniel C Moreira, Eric Bouffet, Ibrahim Qaddoumi.
      
    DOI:  https://doi.org/10.1093/neuonc/noae004
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