Ataxia-telangiectasia mutated (ATM) kinase is a central DNA damage response (DDR) component signalling the presence of DNA double strand breaks (DSBs) to DNA repair, checkpoint and survival pathways. Clinical doses of fractionated radiotherapy directed at tumours kill cells by inducing single strand breaks and DSBs, the latter being particularly lethal to all cells if not repaired. Poor survival rates of glioblastoma multiforme (GBM) patients is attributed to an inability to excise all invasive tumor tissue (if operable) and an intrinsic tumour chemo/radioresistance, which has been linked to elevated ATM activity in glioma stem cells.
ATM inhibition (ATMi) radiosensitises cancer cell lines in vitro and in vivo. ATMi also acutely radiosensitises patient-derived glioma stem cells more effectively than by inhibiting other DDR or cell cycle checkpoint components (PARP, ATR, Chk1). Checkpoint-defective glioblastoma multiforme (GBM) cell lines seem to be particularly radio-sensitised by ATMi. In addition, several studies suggest that normal brain is radioprotected when ATM activity is deficient, suggesting ATM is required for apoptosis in neurons. ATMi in brain may therefore provide a wide therapeutic margin. Furthermore, ATM's role in signalling DNA damage independent redox stress has been linked to promoting neoangiogenesis in tumour vasculature. Taken together, these studies suggest ATM is an extremely attractive target to inhibit during and potentially following radiotherapy. However, one impediment to preclinical and clinical studies is that current ATMi's have limited CNS bioavailability.
We report AZ32 as the first known selective, orally bioavailable blood-brain barrier (BBB) penetrating ATMi probe. AZ32 inhibits the DDR and radiosensitizes p53/checkpoint-defective GBM cells in vitro. Oral daily dosing providing sufficient mouse free brain pharmacokinetic exposures over AZ32's ATM IC50, during just four daily doses of whole brain irradiation results in significant improvement in median overall survival of syngeneic orthotopic mouse glioma models (log-rank AZ32/radiation vs. radiation p = 0.0194). Tumor eradication was confirmed by tumor imaging. This result was recapitulated with a human orthotopic model. These findings support the development of clinical grade BBB-penetrating ATMi as a potential treatment for GBM and potentially other intracranial tumours dosed in combination with fractionated radiotherapy used in standard clinical practice.
Citation Format: Steve T. Durant, Jeremy Karlin, Kurt Pike, Nicola Colclough, N Mukhopadhyay, S F. Ahmad, J M. Bekta, M Tokarz, Catherine Bardelle, Gareth Hughes, Bhavika Patel, Andrew Thomason, Elaine Cadogan, Ian Barrett, Alan Lau, Martin Pass, Kristoffer Valerie. Blood-brain barrier penetrating ATM inhibitor (AZ32) radiosensitises intracranial gliomas in mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3041.