Abstract 3042: The novel Akt inhibitor AZD5363 following radiotherapy improves tumor control in mouse models of head and neck cancer
Authors: Emma J. Searle, Brian Telfer, Duncan Forster, Kaye J. Williams, Barry Davies, Timothy Illidge, Ian Stratford
Journal: Cancer Research (2016)

Abstract Radiation therapy (RT) is an important anti-cancer treatment. Understanding the molecular pathways involved in the response of tumors to RT has led to interest in developing drugs which target these; one such target is Akt. Previous studies support the hypothesis that Akt inhibition might enhance the radiosensitivity of tumors through modification of cellular and micro-environmental factors. AZD5363 is a novel, orally bio-available, ATP competitive inhibitor of Akt and here we have evaluated whether AZD5363 will increase the efficacy of RT in preclinical models of head and neck (H&amp;N) cancer. The ability of AZD5363 to inhibit the Akt pathway was investigated in vitro in 5 H&amp;N cell lines and in vivo (FaDu xenografts) using western blot and ELISA techniques. The effect of AZD5363 on the radiosensitivity in vitro was assessed using clonogenic assays. The FaDu xenograft model was used to test the effect of AZD5363 on tumor growth when used as a sequential treatment (for 7 days before RT) or adjuvant therapy (continuously after RT). RT was given as a 6Gy single dose. The effect of these treatments on the tumor microenvironment prior to and after irradiation was also assessed using FAZA PET/CT, immunohistochemistry and ELISA techniques. AZD5363 effectively inhibited the Akt pathway in in vitro and in vivo. There was no effect on radiosensitivity in vitro when drug was administered in a variety of sequences and durations around RT. In vivo, there was no improvement in tumor control when AZD5363 was given for 7 days before RT. But survival was improved (p = 0.006) when AZD5363 was administered continuously after RT with reduced tumor growth (p = 0.0035, 7 days after RT). There was no effect of drug alone on tumor growth and no difference in the level of tumor hypoxia (measured using FAZA PET/CT or pimonidazole binding) after 7 days AZD5363. Human VEGF and HIF1α levels were reduced (p = 0.0104 and p = 0.002, respectively) after 7 days AZD5363. There was no difference in microvessel density (MVD) prior to RT, but 7 days after, MVD was significantly reduced if adjuvant AZD5363 had been given (p = 0.0317). AZD5363 was also found to effect the rate of proliferation of human umbilical vein endothelial (HUVEC) cells in vitro. AZD5363 effectively improves long term control of FaDu tumors when combined with RT. However, this only occurs when the drug is used in the adjuvant setting. AZD5363 has no effect on the radiosensitivity of H&amp;N cells in vitro, which suggests that the in vivo effects are dependent on the tumor microenvironment. AZD5363 reduces tumor VEGF and HIF1α in an oxygen independent manner and inhibits the rate of proliferation of vascular endothelial cells, effects that would reduce vascular recovery after RT. This is the first time a specific inhibitor of Akt has been reported to have this sequence dependent ability to enhance the effects of RT and has implications for how AZD5363 and potentially other Akt inhibitors are used in combination with RT in the clinic. Citation Format: Emma J. Searle, Brian Telfer, Duncan Forster, Kaye J. Williams, Barry Davies, Timothy Illidge, Ian Stratford. The novel Akt inhibitor AZD5363 following radiotherapy improves tumor control in mouse models of head and neck cancer. [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 3042.