The radiation targeting of PTEN-deficiency in castration-resistant prostate cancer in combination with modulators of DNA damage repair

• Main Author: Hanna, Conor J
• Format: Dissertation
• Language: English
• Published: Queen's University Belfast 2015

Radical radiotherapy, often in combination with hormone ablation, is a safe and effective treatment option for localised or locally-advanced prostate cancer. However, up to 30% of patients with locally advanced PCa will go on to develop biochemical failure, within 5 years, following initial radiotherapy. Improving radiotherapy response is clinically important since patients exhibiting biochemical failure develop castrate-resistant metastatic disease for which there is no curative therapy and median survival is 8-18 months. Loss of the tumour suppressor PTEN function is observed at a high incidence in advanced prostate cancer and is reported to be a prognostic factor for relapse following radiotherapy in locally advanced PCa. Unpublished studies within our group identified PTEN as synthetically lethal with ATM deficiency. We therefore aimed to test the efficacy of ATM inhibition to radiosensitise PTEN-deficient cells. PTEN-isogenic in vitro tumour and normal cell models as well as a Tet-inducible in vivo xenograft prostate model were used in this study. Response to clinically relevant dose's of ionising radiation and ATM kinase inhibitor KU-60019 treatment was assessed using clonogenic survival assays and tumour growth delay studies. The molecular mechanisms mediating selective sensitivity of PTEN-deficient cells to these agents were determined by western blotting, y-H2AX foci. Our results show the role of PTEN in cellular response to IR was both complex and context-dependent. Secondly, combination treatment with KU-6001 9 ATM kinase inhibitor and IR was shown to selectively target PTEN-deficient tumour cells with minimal toxicity to normal prostate RWPE-1 cells. Furthermore, combined treatment significantly inhibited PTEN-deficient tumour growth compared to PTEN-expressing counterparts, with minimal toxicity observed. This project shows A TM inhibition enhances radiation sensitivity of PTEN-deficient tumour cells. The mechanism of this effect appears to involve increased oxidative damage rather than the cells' capacities to repair DNA damage. These findings support the clinical evaluation of ATM inhibitors in combination with radiation in CRPC,