Non-specific HIF1α inhibitors in men receiving androgen deprivation therapy for prostate cancer

1. No. 086 Non-specific HIF1α inhibitors in men receiving androgen deprivation therapy for prostate cancer Weranja Ranasinghe1,2, Shomik Sengupta1, Scott Williams3, Mike Chang1, Arthur Shulkes1, Damien Bolton1, Graham Baldwin1, Oneel Patel1 1.Department of Urology, Austin Health/ University of Melbourne, 2. Royal Melbourne Hospital/North-East Health Wangaratta, 3. Peter MacCullum Cancer Institute, Melbourne Posters Proudly Supported by: Introduction We have previously demonstrated that the expression of Hypoxia-Inducible Factor α (HIF1α) increases the risk of castrate resistance and metastases in patients on androgen deprivation therapy for prostate cancer (PC)[1]. Digoxin, metformin and angiotensin-2 inhibitors have all been shown to inhibit HIF1α in-vitro [2,3,4]. • Results continued • Time to castrate resistance • There was a 2.4 fold increase in the median time to castrate resistance free survival (Fig 1) in patients on HIF1α inhibitors vsnot on HIF1α inhibitors (6.8yrs vs. 2.8yrs) log rank p=0.01) with 5-year resistance free rates of 63% vs. 21% respectively. • On a multivariate Cox regression analysis, there was a68% [HR 0.32 (CI 0.12 – 0.85) p=0.02] in the risk of developing CRPC patients who were on HIF1α inhibitors. • Time to Metastases • Men on HIF1α inhibitors also had a 2 fold increase in the median metastases-free survival compared to those not on inhibitors. (5.1 yrs vs. 2.6 yrs, log rank test p=0.01) (Fig 2) with 5-year resistance-free rates of 43% vs.17.4%, respectively. • On a multivariate Cox regression analysis, there was a 76% reduction [HR 0.24 (CI 0.07 – 0.81) p=0.03] in the risk of developing metastases in patients who were on HIF1α inhibitors. Aim We investigated the effects of these non-specific HIF1α inhibitors on development of castrate resistant prostate cancer (CRPC) and metastases. Log Rank p = 0.01 Fig 1. Kaplan Meier graph of CRPC-free survival Methods A retrospective analysis was conducted of all men who had androgen deprivation therapy (ADT) as first line therapy and received chemotherapy for castrate-resistant prostate cancer at the Austin Hospital from 1983- 2011. The drug histories were obtained from the hospital records and patients on digoxin, metformin or angiotensin-2 inhibitors were identified. Kaplan-Meier analysis and log rank test was performed. Multi-variate Cox-proportional hazard regression were used adjusting for age and gleason score. Conclusions Non-specific HIF1α inhibitors are likely to increase the progression free survival and also reduce the risk of developing CRPC and metastases in patients on androgen deprivation therapy. Further prospective studies are warranted to confirm that these drugs improve the patients outcome specifically through inhibition of HIF1α expression. Log Rank p = 0.01 Fig 2. Kaplan Meier graph of CRPC-free survival Acknowledgements We would like to thank Carmel Murone and Dr. Lee Lewis of the Victorian Cancer Biobank for providing tissue samples. • References • Ranasinghe et al. The role of hypoxia-inducible factor 1α in determining the properties of castrate-resistant prostate cancers. PLoS One. 2013. • Zhang et al. Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth. Proc NatlAcadSci USA 2008. • Takiyama et al. (2011). Tubular injury in a rat model of type 2 diabetes is prevented by metformin: a possible role of HIF-1alpha expression and oxygen metabolism. Diabetes 2011. • Kosaka et al. Ets-1 and hypoxia inducible factor-1alpha inhibition by angiotensin II type-1 receptor blockade in hormone-refractory prostate cancer. Prostate 2010. • . • Results • Ninety-eight patients meeting the criteria were identified. • Twenty patients (20.4%) were on non-specific HIF1α inhibitors. • The average Gleason scores were the same (8) in both groups but patients on HIF1α inhibitors were older (68.9 years vs 64.6 years).