Abstract 6168: Characterization of ATM inhibitor (AZD1390) distribution and pharmacodynamic changes in brain and glioblastoma in preclinical models to inform on mechanism of action

Abstract

Abstract Ataxia telangiectasia mutated (ATM) kinase is a key factor in DNA double strand break response and is constitutively activated in glioblastoma, leading to marked radioresistance [Bartkova, Carruthers] and therefore an attractive radiosensitisation target in this disease. AZD1390, a potent ATM inhibitor optimized to cross the blood brain barrier, is being evaluated with radiotherapy in Phase 1 (NCT03423628). Positron emission tomography (PET) studies demonstrated AZD1390 brain exposure in healthy human subjects. This study characterises ATM inhibitor penetration and distribution in brain and GBM, as well as pharmacodynamic biomarker changes in human orthotopic GBM patient-derived explant (PDX) models. Radiation +/- AZD1390 treatment was evaluated for compound concentration in plasma and relative abundance in brain/ GBM regions by mass spectrometry imaging (MSI). Parallel samples were analysed by immunohistochemistry for biomarkers of DNA damage response and ATM signalling. We show AZD1390 penetrates brain tissue with preferential compound accumulation into tumour. Higher ratios of AZD1390 in GBM versus normal brain correlate with improved efficacy and greater levels of DNA damage. Moreover, AZD1390 in the GBM region was heterogeneously distributed with MSI characterized specific metabolic clusters having varied AZD1390 intensities. As expected, radiation treatment activated ATM signalling (indicated by increase in pRAD50 and γH2AX positive cells) which was effectively inhibited by AZD1390 co-treatment. Our work provides novel insights into ATM inhibitor pharmacokinetics in brain tumours and demonstrates the benefit of using MSI in conjunction with pharmacodynamic markers to provide a more complete picture of AZD1390 mechanism of action for future translational studies on clinical GBM samples. Citation Format: Lenka Oplustil O'Connor, Gregory Hamm, Maria Udriste, Stephanie Ling, Joanne Wilson, Steve Durant, Gareth Hughes, Sabina Cosulich, Wenlin Shao, Martin Pass, Gemma Jones, Andrew Pierce, Richard Goodwin, Mark O'Connor, Carl Barrett, Elizabeth Harrington. Characterization of ATM inhibitor (AZD1390) distribution and pharmacodynamic changes in brain and glioblastoma in preclinical models to inform on mechanism of action [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6168.