Prof Marc Vendrell marc.vendrell@ed.ac.uk
Funding information (students eligible to apply): UK/International students
Project Description
Glioblastoma is the most aggressive primary brain tumor in adults, characterized by poor prognosis and resistance to conventional therapies. A major obstacle in effective GBM treatment is the highly immunosuppressive tumor microenvironment (TME), predominantly shaped by tumor-associated myeloid cells, including microglia and infiltrating monocyte-derived macrophages. These cells support tumor growth, suppress anti-tumor immune responses, and promote resistance to therapy.
Targeting myeloid cells represents a promising and underexploited avenue in glioblastoma therapy. In this project we aim to develop and optimize agents that reprogram these cells in order to dismantle the immunosuppressive shield of GBM and improve patient outcomes.
The ability to accomplish this has been hindered by the lack of molecular tools that can selectively activate in subsets of myeloid cells. We have now invented a new class of chemical strategies that can release therapeutic agents in defined subsets of cells (including myeloid cells) with potential enhanced therapeutic efficacy and minimal off-target effects.
We will utilise new tools in peptide/protein chemistry as well as drug conjugates to generate new advanced therapeutics that can harness the metabolic activity of myeloid cells in glioblastoma. Upon evaluation and optimization, we will finally prepare selected agents for translation and clinical readiness, enabling us to move this technology into early phase clinical trials to provide patient benefit as quickly as possible.
The expected outcomes of our strategy will be to achieve reduction in immunosuppressive myeloid cell populations in the tumor microenvironment, enhanced activation of anti-tumor T cells and increased tumor immunogenicity and build the foundations for future combination strategies integrating immunotherapy and myeloid cell modulation.
Expected training outcomes including generic and transferable skills provided by the supervisory team will include:
- Development of cell-specific, prodrug therapuetic platform for the selection and optimisation of agents.
- Data analysis and management and mining skills.
- Design and characterisation of activatable strategies for caging drug and cell-selective release.
- Cell culture, microscopy, flow cytometry, functional assays and immunohistochemistry.
- Assessment of selected agents in ex vivo human tissues.
- Image analysis (qualitative and quantitative).
- Research ethics and health and safety skills.
- Study IP landscape and freedom to operate. Secure emerging IP, including paper and patent writing.
- Communication skills.
References
- Barth et al. “Enzyme-Activatable Chemokine Conjugates for In Vivo Targeting of Tumor-Associated Macrophages.” Angewandte Chemie 61, 41 (2022): e202207508.
- Bertolini et al. “Chemo-Click: Receptor-Controlled and Bioorthogonal Chemokine Ligation for Real-Time Imaging of Drug-Resistant Leukemic B Cells.” Journal of the American Chemical Society 146, 44 (2024): 30565-30572.
- Nadal-Bufi et al. “Fluorogenic Platform for Real-Time Imaging of Subcellular Payload Release in Antibody-Drug Conjugates.” Journal of the American Chemical Society vol. 147, 9 (2025): 7578-7587. doi:10.1021/jacs.4c16842.
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