Investigating the multifaceted effects of DNA damage response inhibitors on the glioblastoma microenvironment
Supervisors
Anthony Chalmers, School of Cancer Sciences, University of Glasgow
Nigel Jamieson, School of Cancer Services, University of Glasgow
Gerald Thompson, Centre for Clinical Brain Sciences, University of Edinburgh
Paul Brennan, Centre for Clinical Brain Sciences, University of Edinburgh
Industry Partner: AstraZeneca
Summary
Glioblastomas (GBM) are incurable, aggressive brain tumours that are resistant to radiotherapy and chemotherapy and exert immunosuppressive effects that contribute to poor outcomes. Microglia are brain-resident immune cells that promote glioblastoma growth and suppress antitumour immune responses. AstraZeneca has developed a brain-penetrant ATM inhibitor (AZD1390) that is an extremely potent radiosensitizer currently being tested in clinical trials in GBM patients. The Chalmers lab has recently shown that the combination of AZD1390 and radiotherapy causes prolonged depletion of microglia in the mouse brain – raising the possibility that it might enhance the therapeutic effects of radiotherapy in GBM by overcoming tumour resistance and unlock an anti-tumour immune response. Interactions between GBM and the tumour microenvionment (including microglia and other immune cells) are extremely complex and heterogenous, however, and cannot be studied in isolation.
The proposed project will utilize existing immunocompetent intracranial mouse models of GBM and freshly derived patient GBM material cultured as brain slices to interrogate the effects of radiotherapy +/- AZD1390 on the tumour microenvironment, with particular focus on microglia and immune responses. World leading spatial transcriptomic and proteomic techniques in the Jamieson laboratory will be applied with the aim of understanding the mechanisms underpinning therapeutic efficacy and resistance, and identifying biomarkers that might predict which patients would benefit from the AZD1390-radiotherapy combination. A multi-disciplinary, translational supervisory team will comprise Anthony Chalmers (Chair of Clinical Oncology, University of Glasgow), Nigel Jamieson (Professor of Surgery, University of Glasgow), Paul Brennan (Reader in Neurosurgery, University of Edinburgh) and Gerry Thompson (Senior Lecturer in Neuroradiology, University of Edinburgh).