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Preclinical Experimental Therapeutics

Session: Poster Session

EXTH-64 - Establishing a clinically relevant mouse model of mesenchymal glioblastoma for studying TME targeting treatments.

Friday, November 17, 2023
7:30 PM – 9:30 PM PT
Location: Exhibit Hall A/B
Non-CME

    Author(s)

  • Kate Connor

    Royal College of Surgeons in Ireland
    Dublin, Dublin, Ireland

    • Poster Presenter(s)

  • Kieron White

    Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, York Street, Dublin 2
    Dublin, Dublin, Ireland

    • Author(s)

  • James Clerkin

    Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, York Street, Dublin 2
    Dublin, Cork, Ireland

  • LS

    Liam Shiels

    Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, York Street, Dublin 2
    Dublin, Ireland

  • KS

    Kieron J. Sweeney

    Department of Neurosurgery, Beaumont hospital, Dublin
    Dublin, Dublin, Ireland

  • TV

    Thomas Van Brussel

    VIB Center for Cancer Biology, Leuven, Belgium
    Leuven, Belgium

  • IA

    Ingrid Arijs

    Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
    Leuven, Belgium

  • DL

    Diether Lambrechts

    Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium
    Leuven, Belgium

  • GS

    Gautam Shankar

    Translational Cell and Tissue Research Unit, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
    Leuven, Belgium

  • Frederik de Smet

    Translational Cell and Tissue Research Unit, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
    Leuven, Vlaams-Brabant, Belgium

  • DZ

    Dieter Zopf

    Research and Development, Preclinical Research Oncology, Bayer AG, Berlin, Germany.
    Berlin, Germany

  • SM

    Stephen Maher

    Applied Radiation Therapy Trinity (ARTT), Discipline of Radiation Therapy, School of Medicine, Trinity St. James's Cancer Institute, Trinity College Dublin, University of Dublin, Dublin, Ireland
    Dublin, Ireland

  • LM

    Laure Marignol

    Applied Radiation Therapy Trinity (ARTT), Discipline of Radiation Therapy, School of Medicine, Trinity St. James's Cancer Institute, Trinity College Dublin, University of Dublin, Dublin, Ireland.
    Dublin, Ireland

  • PD

    Patrick Dicker

    Epidemiology & Public Health, Royal College of Surgeons in Ireland, Dublin 2
    Dublin, Ireland

  • JP

    Jochen Prehn

    Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, York Street, Dublin 2
    Dublin, Dublin, Ireland

  • DO

    David O'Brien

    Department of Neurosurgery, Beaumont hospital, Dublin
    Dublin, Ireland

  • AB

    Annette T. Byrne

    Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, York Street, Dublin 2
    Dublin, Dublin, Ireland

Historically, pre-clinical GBM models have largely failed to predict response in the clinical setting. Here, we establish a more clinically faithful model using the syngeneic NFpp10a-Luc2 mesenchymal-GBM cell line to study response to resection and temozolomide (TMZ), adjuvant/neo-adjuvant anti-PD1 and Regorafenib (REGO) therapy. Cells were orthotopically implanted in C57BL/6-mice. Response to surgical and therapeutic interventions was assessed using bioluminescence imaging (BLI). Murine Microenvironment cell-population (mMCP)-counter, GSEA and multiple iteractive labelling by antibody neodeposition (MILAN, high-dimensional single-cell multiplex analysis) were employed to characterise treatment-related TME effects. We observed survival advantage in aged mice undergoing resection (resection:33.5 days vs non-resection:18 days; p=0.0166). TMZ/anti-PD1 had no impact on tumour growth (TMZ: p=0.9001, anti-PD1: p=0.7933) or survival (TMZ:p=0.3035, anti-PD1-:p=0.6328). Neo-adjuvant anti-PD1 also conferred no survival advantage in young mice (33 vs 35 days; p=0.9429). REGO/REGO+TMZ treatment conferred no survival benefit in young mice (REGO:p=0.0735 and REGO+TMZ:p=0.3945). mMCP-counter (which estimates the abundance of TME-cell populations from gene-expression data) showed resection upregulated B-cells and mast-cells, whereas TMZ caused a decreased abundance of vessels. Anti-PD1 treatment caused an enrichment of B-cells, mast-cells, and CXCR3 expression (p=0.0045). REGO/TMZ+REGO treatment upregulated cytotoxic-lymphocyte populations. MILAN analysis showed resection increased cytotoxic-T-cells (20.3% vs pre-resection:7%). In contrast, TMZ/REGO monotherapy increased tumour-cells and decreased cytotoxic-T-cells. Anti-PD1 decreased macrophage abundance (39.8% vs control:14.5%). Likewise, TMZ+REGO decreased macrophages (11.3% vs control:35.3%) but upregulated B-cells and vessels. Overall, we have characterised response of the NFpp10a mouse model to resection, TMZ, anti-PD1 and REGO. We have shown that the model is insensitive to chemotherapy and TME-targeting therapies, mirroring patient-response patterns. Nevertheless, we observe transcriptomic and proteomic changes following TME-targeting treatments. Further analyses of these TME-associated resistance properties may help guide novel combinatorial treatment regimens. Overall, the NFpp10a model of mesenchymal GBM may be employed in future pre-clinical studies to accurately guide future clinical trials.