bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2023–02–05
ten papers selected by
Oltea Sampetrean, Keio University
  1. Agent Slows Glioblastoma Tumors in Mice by Blocking Fat Metabolism.
  2. Master kinases extracted from proteogenomic networks in glioblastoma drive cancer subtypes.
  3. Glioblastoma and the search for non-hypothesis driven combination therapeutics in academia.
  4. WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma.
  5. Proteogenomics of diffuse gliomas reveal molecular subtypes associated with specific therapeutic targets and immune-evasion mechanisms.
  6. Integrative multi-omics networks identify PKCδ and DNA-PK as master kinases of glioblastoma subtypes and guide targeted cancer therapy.
  7. Losartan controls immune checkpoint blocker-induced edema and improves survival in glioblastoma mouse models.
  8. Next-generation antigen-presenting cell immune therapeutics for gliomas.
  9. Single-cell spatial immune landscapes of primary and metastatic brain tumours.
  10. An expedited strategy for accurate and timely integrated molecular diagnosis of gliomas.
  1. JAMA. 2023 Feb 01.
    Agent Slows Glioblastoma Tumors in Mice by Blocking Fat Metabolism.
    Howard Larkin.
      
    DOI:  https://doi.org/10.1001/jama.2023.0741
  2. Nat Cancer. 2023 Feb 02.
    Master kinases extracted from proteogenomic networks in glioblastoma drive cancer subtypes.
      
    DOI:  https://doi.org/10.1038/s43018-022-00511-w
  3. Front Oncol. 2022 ;12 1075559
    Glioblastoma and the search for non-hypothesis driven combination therapeutics in academia.
    Timothy Johanssen, Laura McVeigh, Sara Erridge, Geoffrey Higgins, Joelle Straehla, Margaret Frame, Tero Aittokallio, Neil O Carragher, Daniel Ebner.
      Glioblastoma (GBM) remains a cancer of high unmet clinical need. Current standard of care for GBM, consisting of maximal surgical resection, followed by ionisation radiation (IR) plus concomitant and adjuvant temozolomide (TMZ), provides less than 15-month survival benefit. Efforts by conventional drug discovery to improve overall survival have failed to overcome challenges presented by inherent tumor heterogeneity, therapeutic resistance attributed to GBM stem cells, and tumor niches supporting self-renewal. In this review we describe the steps academic researchers are taking to address these limitations in high throughput screening programs to identify novel GBM combinatorial targets. We detail how they are implementing more physiologically relevant phenotypic assays which better recapitulate key areas of disease biology coupled with more focussed libraries of small compounds, such as drug repurposing, target discovery, pharmacologically active and novel, more comprehensive anti-cancer target-annotated compound libraries. Herein, we discuss the rationale for current GBM combination trials and the need for more systematic and transparent strategies for identification, validation and prioritisation of combinations that lead to clinical trials. Finally, we make specific recommendations to the preclinical, small compound screening paradigm that could increase the likelihood of identifying tractable, combinatorial, small molecule inhibitors and better drug targets specific to GBM.
    Keywords:  drug target combination; glioblastoma; glioblastoma stem cell; high throughput screening (HTS); hypoxia; radiotherapy; temozolamide
    DOI:  https://doi.org/10.3389/fonc.2022.1075559
  4. Genes Dev. 2023 Feb 02.
    WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma.
    Kelly Mitchell, Samuel A Sprowls, Sonali Arora, Sajina Shakya, Daniel J Silver, Christopher M Goins, Lisa Wallace, Gustavo Roversi, Rachel Schafer, Kristen Kay, Tyler E Miller, Adam Lauko, John Bassett, Anjali Kashyap, Jonathan D'Amato Kass, Erin E Mulkearns-Hubert, Sadie Johnson, Joseph Alvarado, Jeremy N Rich, Eric C Holland, Patrick J Paddison, Anoop P Patel, Shaun R Stauffer, Christopher G Hubert, Justin D Lathia.
      Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors driven by populations of cancer stem cells (CSCs). However, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy-resistant niche and identified WDR5 as indispensable for this population. WDR5 is a component of the WRAD complex, which promotes SET1 family-mediated Lys4 methylation of histone H3 (H3K4me), associated with positive regulation of transcription. In GBM CSCs, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, including the POU5F1(OCT4)::SOX2 motif. Use of a SOX2/OCT4 reporter demonstrated that WDR5 inhibitor treatment diminished cells with high reporter activity. Furthermore, WDR5 inhibitor treatment and WDR5 knockdown altered the stem cell state, disrupting CSC in vitro growth and self-renewal, as well as in vivo tumor growth. These findings highlight the role of WDR5 and the WRAD complex in maintaining the CSC state and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers.
    Keywords:  epigenetics; glioblastoma; stem cell
    DOI:  https://doi.org/10.1101/gad.349803.122
  5. Nat Commun. 2023 Jan 31. 14(1): 505
    Proteogenomics of diffuse gliomas reveal molecular subtypes associated with specific therapeutic targets and immune-evasion mechanisms.
    Yunzhi Wang, Rongkui Luo, Xuan Zhang, Hang Xiang, Bing Yang, Jinwen Feng, Mengjie Deng, Peng Ran, Akesu Sujie, Fan Zhang, Jiajun Zhu, Subei Tan, Tao Xie, Pin Chen, Zixiang Yu, Yan Li, Dongxian Jiang, Xiaobiao Zhang, Jian-Yuan Zhao, Yingyong Hou, Chen Ding.
      Diffuse gliomas are devastating brain tumors. Here, we perform a proteogenomic profiling of 213 retrospectively collected glioma tumors. Proteogenomic analysis reveals the downstream biological events leading by EGFR-, IDH1-, TP53-mutations. The comparative analysis illustrates the distinctive features of GBMs and LGGs, indicating CDK2 inhibitor might serve as a promising drug target for GBMs. Further proteogenomic integrative analysis combined with functional experiments highlight the cis-effect of EGFR alterations might lead to glioma tumor cell proliferation through ERK5 medicates nucleotide synthesis process. Proteome-based stratification of gliomas defines 3 proteomic subgroups (S-Ne, S-Pf, S-Im), which could serve as a complement to WHO subtypes, and would provide the essential framework for the utilization of specific targeted therapies for particular glioma subtypes. Immune clustering identifies three immune subtypes with distinctive immune cell types. Further analysis reveals higher EGFR alteration frequencies accounts for elevation of immune check point protein: PD-L1 and CD70 in T-cell infiltrated tumors.
    DOI:  https://doi.org/10.1038/s41467-023-36005-1
  6. Nat Cancer. 2023 Feb 02.
    Integrative multi-omics networks identify PKCδ and DNA-PK as master kinases of glioblastoma subtypes and guide targeted cancer therapy.
    Simona Migliozzi, Young Taek Oh, Mohammad Hasanain, Luciano Garofano, Fulvio D'Angelo, Ryan D Najac, Alberto Picca, Franck Bielle, Anna Luisa Di Stefano, Julie Lerond, Jann N Sarkaria, Michele Ceccarelli, Marc Sanson, Anna Lasorella, Antonio Iavarone.
      Despite producing a panoply of potential cancer-specific targets, the proteogenomic characterization of human tumors has yet to demonstrate value for precision cancer medicine. Integrative multi-omics using a machine-learning network identified master kinases responsible for effecting phenotypic hallmarks of functional glioblastoma subtypes. In subtype-matched patient-derived models, we validated PKCδ and DNA-PK as master kinases of glycolytic/plurimetabolic and proliferative/progenitor subtypes, respectively, and qualified the kinases as potent and actionable glioblastoma subtype-specific therapeutic targets. Glioblastoma subtypes were associated with clinical and radiomics features, orthogonally validated by proteomics, phospho-proteomics, metabolomics, lipidomics and acetylomics analyses, and recapitulated in pediatric glioma, breast and lung squamous cell carcinoma, including subtype specificity of PKCδ and DNA-PK activity. We developed a probabilistic classification tool that performs optimally with RNA from frozen and paraffin-embedded tissues, which can be used to evaluate the association of therapeutic response with glioblastoma subtypes and to inform patient selection in prospective clinical trials.
    DOI:  https://doi.org/10.1038/s43018-022-00510-x
  7. Proc Natl Acad Sci U S A. 2023 Feb 07. 120(6): e2219199120
    Losartan controls immune checkpoint blocker-induced edema and improves survival in glioblastoma mouse models.
    Meenal Datta, Sampurna Chatterjee, Elizabeth M Perez, Simon Gritsch, Sylvie Roberge, Mark Duquette, Ivy X Chen, Kamila Naxerova, Ashwin S Kumar, Mitrajit Ghosh, Kyrre E Emblem, Mei R Ng, William W Ho, Pragya Kumar, Shanmugarajan Krishnan, Xinyue Dong, Maria C Speranza, Martha R Neagu, J Bryan Iorgulescu, Raymond Y Huang, Gilbert Youssef, David A Reardon, Arlene H Sharpe, Gordon J Freeman, Mario L Suvà, Lei Xu, Rakesh K Jain.
      Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma trials. Here, we found that ICBs induce cerebral edema in some patients and mice with glioblastoma. Through single-cell RNA sequencing, intravital imaging, and CD8+ T cell blocking studies in mice, we demonstrated that this edema results from an inflammatory response following antiprogrammed death 1 (PD1) antibody treatment that disrupts the blood-tumor barrier. Used in lieu of immunosuppressive corticosteroids, the angiotensin receptor blocker losartan prevented this ICB-induced edema and reprogrammed the tumor microenvironment, curing 20% of mice which increased to 40% in combination with standard of care treatment. Using a bihemispheric tumor model, we identified a "hot" tumor immune signature prior to losartan+anti-PD1 therapy that predicted long-term survival. Our findings provide the rationale and associated biomarkers to test losartan with ICBs in glioblastoma patients.
    Keywords:  biomarkers; glioblastoma; immune checkpoint blockers; immune-related adverse events; tumor microenvironment
    DOI:  https://doi.org/10.1073/pnas.2219199120
  8. J Clin Invest. 2023 Feb 01. pii: e163449. [Epub ahead of print]133(3):
    Next-generation antigen-presenting cell immune therapeutics for gliomas.
    Catalina Lee-Chang, Maciej S Lesniak.
      Antigen presentation machinery and professional antigen-presenting cells (APCs) are fundamental for an efficacious immune response against cancers, especially in the context of T cell-centric immunotherapy. Dendritic cells (DCs), the gold standard APCs, play a crucial role in initiating and maintaining a productive antigen-specific adaptive immunity. In recent decades, ex vivo-differentiated DCs from circulating CD14+ monocytes have become the reference for APC-based immunotherapy. DCs loaded with tumor-associated antigens, synthetic peptides, or RNA activate T cells with antitumor properties. This strategy has paved the way for the development of alternative antigen-presenting vaccination strategies, such as monocytes, B cells, and artificial APCs, that have shown effective therapeutic outcomes in preclinical cancer models. The search for alternative APC platforms was initiated by the overall limited clinical impact of DC vaccines, especially in indications such as gliomas, a primary brain tumor known for resistance to any immune intervention. In this Review, we navigate the APC immune therapeutics' past, present, and future in the context of primary brain tumors.
    DOI:  https://doi.org/10.1172/JCI163449
  9. Nature. 2023 Feb 01.
    Single-cell spatial immune landscapes of primary and metastatic brain tumours.
    Elham Karimi, Miranda W Yu, Sarah M Maritan, Lucas J M Perus, Morteza Rezanejad, Mark Sorin, Matthew Dankner, Parvaneh Fallah, Samuel Doré, Dongmei Zuo, Benoit Fiset, Daan J Kloosterman, LeeAnn Ramsay, Yuhong Wei, Stephanie Lam, Roa Alsajjan, Ian R Watson, Gloria Roldan Urgoiti, Morag Park, Dieta Brandsma, Donna L Senger, Jennifer A Chan, Leila Akkari, Kevin Petrecca, Marie-Christine Guiot, Peter M Siegel, Daniela F Quail, Logan A Walsh.
      Single-cell technologies have enabled the characterization of the tumour microenvironment at unprecedented depth and have revealed vast cellular diversity among tumour cells and their niche. Anti-tumour immunity relies on cell-cell relationships within the tumour microenvironment1,2, yet many single-cell studies lack spatial context and rely on dissociated tissues3. Here we applied imaging mass cytometry to characterize the immunological landscape of 139 high-grade glioma and 46 brain metastasis tumours from patients. Single-cell analysis of more than 1.1 million cells across 389 high-dimensional histopathology images enabled the spatial resolution of immune lineages and activation states, revealing differences in immune landscapes between primary tumours and brain metastases from diverse solid cancers. These analyses revealed cellular neighbourhoods associated with survival in patients with glioblastoma, which we leveraged to identify a unique population of myeloperoxidase (MPO)-positive macrophages associated with long-term survival. Our findings provide insight into the biology of primary and metastatic brain tumours, reinforcing the value of integrating spatial resolution to single-cell datasets to dissect the microenvironmental contexture of cancer.
    DOI:  https://doi.org/10.1038/s41586-022-05680-3
  10. Neuro Oncol. 2023 Feb 01. pii: noad007. [Epub ahead of print]
    An expedited strategy for accurate and timely integrated molecular diagnosis of gliomas.
    Timothy A Gregory, Garret L Williford, Jacob M Maronge, Kristin Alfaro, Gregory N Fuller, John de Groot, Vinay K Puduvalli, Leomar Y Ballester, Nazanin K Majd.
      
    DOI:  https://doi.org/10.1093/neuonc/noad007
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