Investigating the Multifaceted Effects of DNA Damage Response Inhibitors on the Glioblastoma Microenvironment

Glioblastoma (GBM) is the most common adult-type diffuse glioma and is associated with the worst prognosis of all solid tumours with an average life expectancy of 12-15 months. Despite advancements in radiotherapy, the standard of care (SoC) of GBM has remained largely unaltered since the inception of the Strupp protocol in 2005. This involves maximal surgical resection followed by concurrent chemoradiotherapy, pairing fractionated external bean radiotherapy along with strong, often adjuvated, alkylating chemotherapeutics, namely Temozolomide.

GBM is inherently radioresistant and employs multiple resistance mechanisms which limit the effectiveness of the SoC which remains largely palliative.

Resistance mechanisms include inadequate blood-brain barrier passage, high intra- and intertumoral heterogeneity, radioresistant glioma stem cells, and pathway redundancy. The heterogeneous tumour microenvironment (TME) has been found to contribute greatly to treatment resistance and therefore the response to therapy. The GBM TME, which includes resident immune cells like microglia, plays a critical role in tumour progression and treatment resistance.

Microglia, the brain's resident immune cells, have been implicated in promoting tumour growth and evading immune surveillance, thus contributing to the poor prognosis observed in GBM patients.

To address this therapeutic challenge, AstraZeneca has developed AZD1390, a brain-penetrant ATM inhibitor currently under investigation for safety and tolerability for GBM patients (NCT03423628). In preclinical models, AZD1390 has shown to be a selective and potent ATM inhibitor, demonstrating the ability to enhance the effects of radiotherapy, acting as a radiosensitiser.

Early studies from the Chalmers lab have revealed that combining AZD1390 with radiotherapy leads to a prolonged depletion of microglia populations in mouse models. This raises an exciting hypothesis: that AZD1390, in combination with radiotherapy, could enhance anti-tumour immune responses and potentially overcome GBM's resistance to treatment by disrupting the tumour-supporting microenvironment.

This project seeks to further investigate the impact of AZD1390 on the GBM microenvironment by utilising immunocompetent/deficient intracranial mouse models, validating findings in ex vivo human GBM samples. This dual approach allows for a more comprehensive study of how AZD1390, in combination with radiotherapy, affects tumour-immune interactions, particularly focusing on microglia and other immune cells.

To unravel the complex dynamics within the GBM TME, this project will employ cutting-edge spatial omics techniques in addition to advanced imaging methods, to map gene and protein expression patterns across treated tumours. These analyses, conducted in collaboration with the Jamieson laboratory, aim to elucidate the molecular mechanisms driving the efficacy of AZD1390 and radiotherapy.

By integrating these spatial approaches with imaging data, the project will provide insights into how therapeutic responses manifest at the cellular and tissue levels. In addition, the project will collaborate with AstraZeneca to explore the pharmacokinetics and drug distribution of AZD1390 using mass spectrometric imaging techniques.

Ultimately, this project aspires to identify potential predictive biomarkers that could improve patient stratification. By integrating multi-disciplinary expertise from oncology, surgery, neurology, and radiology, this project will offer a comprehensive investigation into the biological underpinnings of GBM treatment responses and resistance mechanisms.

The knowledge gained may pave the way for more targeted, personalised treatment strategies that could improve outcomes for patients with this devastating disease.