bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2022–10–02
ten papers selected by
Oltea Sampetrean, Keio University
  1. Progression of Glioblastoma Is Impaired by VEGF Inhibition and Imipramine.
  2. GD2-targeting CAR-T cells enhanced by transgenic IL-15 expression are an effective and clinically feasible therapy for glioblastoma.
  3. Development of Experimental Three-Dimensional Tumor Models to Study Glioblastoma Cancer Stem Cells and Tumor Microenvironment.
  4. The proteomic landscape of glioblastoma recurrence reveals novel and targetable immunoregulatory drivers.
  5. Characterization of the minimal residual disease state reveals distinct evolutionary trajectories of human glioblastoma.
  6. Metabolic remodeling of pyrimidine synthesis pathway and serine synthesis pathway in human glioblastoma.
  7. New Strategy May Thwart Glioblastoma Resistance.
  8. Clinical and NGS predictors of response to regorafenib in recurrent glioblastoma.
  9. CRY2 isoform selectivity of a circadian clock modulator with antiglioblastoma efficacy.
  10. Development of GPC2-directed chimeric antigen receptors using mRNA for pediatric brain tumors.
  1. Cancer Discov. 2022 Sep 30. OF1
    Progression of Glioblastoma Is Impaired by VEGF Inhibition and Imipramine.
      Dual VEGF inhibitor and tricyclic antidepressant treatment reduces GBM tumor growth and promotes immunity.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-173
  2. J Immunother Cancer. 2022 Sep;pii: e005187. [Epub ahead of print]10(9):
    GD2-targeting CAR-T cells enhanced by transgenic IL-15 expression are an effective and clinically feasible therapy for glioblastoma.
    Tessa Gargett, Lisa M Ebert, Nga T H Truong, Paris M Kollis, Kristyna Sedivakova, Wenbo Yu, Erica C F Yeo, Nicole L Wittwer, Briony L Gliddon, Melinda N Tea, Rebecca Ormsby, Santosh Poonnoose, Jake Nowicki, Orazio Vittorio, David S Ziegler, Stuart M Pitson, Michael P Brown.
       BACKGROUND: Aggressive primary brain tumors such as glioblastoma are uniquely challenging to treat. The intracranial location poses barriers to therapy, and the potential for severe toxicity. Effective treatments for primary brain tumors are limited, and 5-year survival rates remain poor. Immune checkpoint inhibitor therapy has transformed treatment of some other cancers but has yet to significantly benefit patients with glioblastoma. Early phase trials of chimeric antigen receptor (CAR) T-cell therapy in patients with glioblastoma have demonstrated that this approach is safe and feasible, but with limited evidence of its effectiveness. The choices of appropriate target antigens for CAR-T-cell therapy also remain limited.
    METHODS: We profiled an extensive biobank of patients' biopsy tissues and patient-derived early passage glioma neural stem cell lines for GD2 expression using immunomicroscopy and flow cytometry. We then employed an approved clinical manufacturing process to make CAR- T cells from patients with peripheral blood of glioblastoma and diffuse midline glioma and characterized their phenotype and function in vitro. Finally, we tested intravenously administered CAR-T cells in an aggressive intracranial xenograft model of glioblastoma and used multicolor flow cytometry, multicolor whole-tissue immunofluorescence and next-generation RNA sequencing to uncover markers associated with effective tumor control.
    RESULTS: Here we show that the tumor-associated antigen GD2 is highly and consistently expressed in primary glioblastoma tissue removed at surgery. Moreover, despite patients with glioblastoma having perturbations in their immune system, highly functional GD2-specific CAR-T cells can be produced from their peripheral T cells using an approved clinical manufacturing process. Finally, after intravenous administration, GD2-CAR-T cells effectively infiltrated the brain and controlled tumor growth in an aggressive orthotopic xenograft model of glioblastoma. Tumor control was further improved using CAR-T cells manufactured with a clinical retroviral vector encoding an interleukin-15 transgene alongside the GD2-specific CAR. These CAR-T cells achieved a striking 50% complete response rate by bioluminescence imaging in established intracranial tumors.
    CONCLUSIONS: Targeting GD2 using a clinically deployed CAR-T-cell therapy has a sound scientific and clinical rationale as a treatment for glioblastoma and other aggressive primary brain tumors.
    Keywords:  brain neoplasms; immunotherapy, adoptive; receptors, chimeric antigen
    DOI:  https://doi.org/10.1136/jitc-2022-005187
  3. Methods Mol Biol. 2023 ;2572 117-127
    Development of Experimental Three-Dimensional Tumor Models to Study Glioblastoma Cancer Stem Cells and Tumor Microenvironment.
    Henry Ruiz-Garcia, Natanael Zarco, Fumihiro Watanabe, Virginea De Araujo Farias, Paola Suarez-Meade, Hugo Guerrero-Cazares, Jaime Imitola, Alfredo Quinones-Hinojosa, Daniel Trifiletti.
      Glioblastoma (GBM) is the most common and dismal primary brain tumor. Unfortunately, despite multidisciplinary treatment, most patients will perish approximately 15 months after diagnosis. For this reason, there is an urgent need to improve our understanding of GBM tumor biology and develop novel therapies that can achieve better clinical outcomes. In this setting, three-dimensional tumor models have risen as more appropriate preclinical tools when compared to traditional cell cultures, given that two-dimensional (2D) cultures have failed to accurately recapitulate tumor biology and translate preclinical findings into patient benefits. Three-dimensional cultures using neurospheres, organoids, and organotypic better resemble original tumor genetic and epigenetic profiles, maintaining tumor microenvironment characteristics and mimicking cell-cell and cell-matrix interactions. This chapter summarizes our methods to generate well-characterized glioblastoma neurospheres, organoids, and organotypics.
    Keywords:  Glioblastoma; Neurosphere; Organoids; Organotypics; Stem cell
    DOI:  https://doi.org/10.1007/978-1-0716-2703-7_9
  4. Acta Neuropathol. 2022 Sep 30.
    The proteomic landscape of glioblastoma recurrence reveals novel and targetable immunoregulatory drivers.
    Nazanin Tatari, Shahbaz Khan, Julie Livingstone, Kui Zhai, Dillon Mckenna, Vladimir Ignatchenko, Chirayu Chokshi, William D Gwynne, Manoj Singh, Spencer Revill, Nicholas Mikolajewicz, Chenghao Zhu, Jennifer Chan, Cynthia Hawkins, Jian-Qiang Lu, John P Provias, Kjetil Ask, Sorana Morrissy, Samuel Brown, Tobias Weiss, Michael Weller, Hong Han, Jeffrey N Greenspoon, Jason Moffat, Chitra Venugopal, Paul C Boutros, Sheila K Singh, Thomas Kislinger.
      Glioblastoma (GBM) is characterized by extensive cellular and genetic heterogeneity. Its initial presentation as primary disease (pGBM) has been subject to exhaustive molecular and cellular profiling. By contrast, our understanding of how GBM evolves to evade the selective pressure of therapy is starkly limited. The proteomic landscape of recurrent GBM (rGBM), which is refractory to most treatments used for pGBM, are poorly known. We, therefore, quantified the transcriptome and proteome of 134 patient-derived pGBM and rGBM samples, including 40 matched pGBM-rGBM pairs. GBM subtypes transition from pGBM to rGBM towards a preferentially mesenchymal state at recurrence, consistent with the increasingly invasive nature of rGBM. We identified immune regulatory/suppressive genes as important drivers of rGBM and in particular 2-5-oligoadenylate synthase 2 (OAS2) as an essential gene in recurrent disease. Our data identify a new class of therapeutic targets that emerge from the adaptive response of pGBM to therapy, emerging specifically in recurrent disease and may provide new therapeutic opportunities absent at pGBM diagnosis.
    Keywords:  Glioblastoma; Immunosuppression; OAS2; Proteomics
    DOI:  https://doi.org/10.1007/s00401-022-02506-4
  5. Cell Rep. 2022 Sep 27. pii: S2211-1247(22)01261-X. [Epub ahead of print]40(13): 111420
    Characterization of the minimal residual disease state reveals distinct evolutionary trajectories of human glioblastoma.
    Maleeha A Qazi, Sabra K Salim, Kevin R Brown, Nicholas Mikolajewicz, Neil Savage, Hong Han, Minomi K Subapanditha, David Bakhshinyan, Allison Nixon, Parvez Vora, Kimberly Desmond, Chirayu Chokshi, Mohini Singh, Amanda Khoo, Andrew Macklin, Shahbaz Khan, Nazanin Tatari, Neil Winegarden, Laura Richards, Trevor Pugh, Nicholas Bock, Alireza Mansouri, Chitra Venugopal, Thomas Kislinger, Sidhartha Goyal, Jason Moffat, Sheila K Singh.
      Recurrence of solid tumors renders patients vulnerable to advanced, treatment-refractory disease state with mutational and oncogenic landscape distinctive from initial diagnosis. Improving outcomes for recurrent cancers requires a better understanding of cell populations that expand from the post-therapy, minimal residual disease (MRD) state. We profile barcoded tumor stem cell populations through therapy at tumor initiation, MRD, and recurrence in our therapy-adapted, patient-derived xenograft models of glioblastoma (GBM). Tumors show distinct patterns of recurrence in which clonal populations exhibit either a pre-existing fitness advantage or an equipotency fitness acquired through therapy. Characterization of the MRD state by single-cell and bulk RNA sequencing reveals a tumor-intrinsic immunomodulatory signature with prognostic significance at the transcriptomic level and in proteomic analysis of cerebrospinal fluid (CSF) collected from patients with GBM. Our results provide insight into the innate and therapy-driven dynamics of human GBM and the prognostic value of interrogating the MRD state in solid cancers.
    Keywords:  CP: Cancer; cellular barcoding; glioblastoma; glioblastoma stem cells; liquid biopsy; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.celrep.2022.111420
  6. Sci Rep. 2022 Sep 29. 12(1): 16277
    Metabolic remodeling of pyrimidine synthesis pathway and serine synthesis pathway in human glioblastoma.
    Akira Nakamizo, Yuichiro Miyamatsu, Haruka Hirose, Toshiyuki Amano, Satoshi Matsuo, Minako Fujiwara, Teppei Shimamura, Koji Yoshimoto.
      Glioblastoma is the most common brain tumor with dismal outcomes in adults. Metabolic remodeling is now widely acknowledged as a hallmark of cancer cells, but glioblastoma-specific metabolic pathways remain unclear. Here we show, using a large-scale targeted proteomics platform and integrated molecular pathway-level analysis tool, that the de novo pyrimidine synthesis pathway and serine synthesis pathway (SSP) are the major enriched pathways in vivo for patients with glioblastoma. Among the enzymes associated with nucleotide synthesis, RRM1 and NME1 are significantly upregulated in glioblastoma. In the SSP, SHMT2 and PSPH are upregulated but the upstream enzyme PSAT1 is downregulated in glioblastoma. Kaplan-Meier curves of overall survival for the GSE16011 and The Cancer Genome Atlas datasets revealed that high SSP activity correlated with poor outcome. Enzymes relating to the pyrimidine synthesis pathway and SSP might offer therapeutic targets for new glioblastoma treatments.
    DOI:  https://doi.org/10.1038/s41598-022-20613-w
  7. Cancer Discov. 2022 Sep 27. OF1
    New Strategy May Thwart Glioblastoma Resistance.
      A recent study demonstrates a new approach for targeting glioblastomas with faulty DNA repair pathways. Researchers synthesized a compound called KL-50 that creates a DNA lesion that becomes fatal to the cell if it is not repaired. KL-50 killed glioblastoma cells in which one key DNA repair protein was missing and an alternate repair mechanism didn't work. The molecule also suppressed tumor growth in mice with implanted glioblastomas.
    DOI:  https://doi.org/10.1158/2159-8290.CD-NB2022-0055
  8. Sci Rep. 2022 Sep 28. 12(1): 16265
    Clinical and NGS predictors of response to regorafenib in recurrent glioblastoma.
    Silvia Chiesa, Antonella Mangraviti, Maurizio Martini, Tonia Cenci, Ciro Mazzarella, Simona Gaudino, Serena Bracci, Antonella Martino, Giuseppe M Della Pepa, Martina Offi, Marco Gessi, Rosellina Russo, Matia Martucci, Francesco Beghella Bartoli, Luigi M Larocca, Liverana Lauretti, Alessandro Olivi, Roberto Pallini, Mario Balducci, Quintino Giorgio D'Alessandris.
      Predictive factors for response to regorafenib in recurrent glioblastoma, IDH-wildtype, are scarcely recognized. The objective of this study was to identify molecular predictive factors for response to regorafenib using a clinically available platform. We analyzed a prospective cohort of 30 patients harboring recurrent glioblastoma, IDH-wildtype, and treated with regorafenib. Next-generation sequencing (NGS) analysis was performed on DNA extracted from paraffin-embedded tissues using a clinically available platform. Moreover, MGMT methylation and EGFRvIII expression analyses were performed. Six-month progression-free survival (PFS) was 30% and median overall survival (OS) was 7.5 months, in line with literature data. NGS analysis revealed a mutation in the EGFR pathway in 18% of cases and a mutation in the mitogen-activated protein-kinase (MAPK) pathway in 18% of cases. In the remaining cases, no mutations were detected. Patients carrying MAPK pathway mutation had a poor response to regorafenib treatment, with a significantly shorter PFS and a nonsignificantly shorter OS compared to EGFR-mutated patients (for PFS, 2.5 vs 4.5 months, p = 0.0061; for OS, 7 vs 9 months, p = 0.1076). Multivariate analysis confirmed that MAPK pathway mutations independently predicted a shorter PFS after regorafenib treatment (p = 0.0188). The negative prognostic role of MAPK pathway alteration was reinforced when we combined EGFR-mutated with EGFRvIII-positive cases. Recurrent glioblastoma tumors with an alteration in MAPK pathway could belong to the mesenchymal subtype and respond poorly to regorafenib treatment, while EGFR-altered cases have a better response to regorafenib. We thus provide a molecular selection criterion easy to implement in the clinical practice.
    DOI:  https://doi.org/10.1038/s41598-022-20417-y
  9. Proc Natl Acad Sci U S A. 2022 Oct 04. 119(40): e2203936119
    CRY2 isoform selectivity of a circadian clock modulator with antiglioblastoma efficacy.
    Simon Miller, Manish Kesherwani, Priscilla Chan, Yoshiko Nagai, Moeri Yagi, Jamie Cope, Florence Tama, Steve A Kay, Tsuyoshi Hirota.
      The mammalian cryptochrome isoforms, CRY1 and CRY2, are core circadian clock regulators that work redundantly. Recent studies revealed distinct roles of these closely related homologs in clock output pathways. Isoform-selective control of CRY1 and CRY2 is critical for further understanding their redundant and distinct roles. KL001 was the first identified small-molecule CRY modulator that activates both CRY1 and CRY2. SHP656 is an orally available KL001 derivative and has shown efficacy in blood glucose control and inhibition of glioblastoma stem cell (GSC) growth in animal models. However, CRY isoform selectivity of SHP656 was uncharacterized, limiting understanding of the roles of CRY1 and CRY2. Here, we report the elucidation of CRY2 selectivity of SHP656. SHP656 lengthened cellular circadian period in a CRY2-dependent manner and selectively interacted with CRY2. By determining the X-ray crystal structure of CRY2 in complex with SHP656 and performing molecular dynamics simulations, we elucidated compound interaction mechanisms. SHP656 binding was compatible with the intrinsic CRY2 gatekeeper W417 "in" orientation and also a close "further in" conformation. Perturbation of W417 interaction with the lid loop resulted in a reduced effect of SHP656 on CRY2, supporting an important role of gatekeeper orientation in isoform selectivity. We also identified the R form of SHP656 (called SHP1703) as the active isomer. Treatment with SHP1703 effectively reduced GSC viability. Our results suggest a direct role of CRY2 in glioblastoma antitumorigenesis and provide a rationale for the selective modulation of CRY isoforms in the therapeutic treatment of glioblastoma and other circadian clock-related diseases.
    Keywords:  X-ray crystallography; circadian clock; cryptochromes; glioblastoma; small-molecule modulators
    DOI:  https://doi.org/10.1073/pnas.2203936119
  10. J Immunother Cancer. 2022 Sep;pii: e004450. [Epub ahead of print]10(9):
    Development of GPC2-directed chimeric antigen receptors using mRNA for pediatric brain tumors.
    Jessica B Foster, Crystal Griffin, Jo Lynne Rokita, Allison Stern, Cameron Brimley, Komal Rathi, Maria V Lane, Samantha N Buongervino, Tiffany Smith, Peter J Madsen, Daniel Martinez, Alberto Delaidelli, Poul H Sorensen, Robert J Wechsler-Reya, Katalin Karikó, Phillip B Storm, David M Barrett, Adam C Resnick, John M Maris, Kristopher R Bosse.
       BACKGROUND: Pediatric brain tumors are the leading cause of cancer death in children with an urgent need for innovative therapies. Glypican 2 (GPC2) is a cell surface oncoprotein expressed in neuroblastoma for which targeted immunotherapies have been developed. This work aimed to characterize GPC2 expression in pediatric brain tumors and develop an mRNA CAR T cell approach against this target.
    METHODS: We investigated GPC2 expression across a cohort of primary pediatric brain tumor samples and cell lines using RNA sequencing, immunohistochemistry, and flow cytometry. To target GPC2 in the brain with adoptive cellular therapies and mitigate potential inflammatory neurotoxicity, we used optimized mRNA to create transient chimeric antigen receptor (CAR) T cells. We developed four mRNA CAR T cell constructs using the highly GPC2-specific fully human D3 single chain variable fragment for preclinical testing.
    RESULTS: We identified high GPC2 expression across multiple pediatric brain tumor types including medulloblastomas, embryonal tumors with multilayered rosettes, other central nervous system embryonal tumors, as well as definable subsets of highly malignant gliomas. We next validated and prioritized CAR configurations using in vitro cytotoxicity assays with GPC2-expressing neuroblastoma cells, where the light-to-heavy single chain variable fragment configurations proved to be superior. We expanded the testing of the two most potent GPC2-directed CAR constructs to GPC2-expressing medulloblastoma and high-grade glioma cell lines, showing significant GPC2-specific cell death in multiple models. Finally, biweekly locoregional delivery of 2-4 million GPC2-directed mRNA CAR T cells induced significant tumor regression in an orthotopic medulloblastoma model and significantly prolonged survival in an aggressive orthotopic thalamic diffuse midline glioma xenograft model. No GPC2-directed CAR T cell related neurologic or systemic toxicity was observed.
    CONCLUSION: Taken together, these data show that GPC2 is a highly differentially expressed cell surface protein on multiple malignant pediatric brain tumors that can be targeted safely with local delivery of mRNA CAR T cells, laying the framework for the clinical translation of GPC2-directed immunotherapies for pediatric brain tumors.
    Keywords:  Brain Neoplasms; Cell Engineering; Central Nervous System Neoplasms; Immunotherapy; Pediatrics
    DOI:  https://doi.org/10.1136/jitc-2021-004450
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