The effects of nonspecific HIF1α inhibitors on development of castrate resistance and metastases in prostate cancer

Weranja K B Ranasinghe,Graham Baldwin,Arthur Shulkes,Shomik Sengupta,Scott Williams,Mike Chang,Damien M Bolton,Oneel Patel

doi:10.1002/cam4.189

Abstract

Expression of hypoxia-inducible factor (HIF)1α increases the risk of castrate-resistant prostate cancer (CRPC) and metastases in patients on androgen deprivation therapy (ADT) for prostate cancer (PC). We aimed to investigate the effects of nonspecific HIF1α inhibitors (Digoxin, metformin, and angiotensin-2 receptor blockers) on development of CRPC and metastases while on ADT. A retrospective review of prospectively collected medical records was conducted of all men who had continuous ADT as first-line therapy for CRPC at the Austin Hospital from 1983 to 2011. Association between HIF1α inhibitor medications and time to develop CRPC was investigated using actuarial statistics. Ninety-eight patients meeting the criteria were identified. Eighteen patients (21.4%) were treated with the nonspecific HIF1α inhibitors. Both groups had similar characteristics, apart from patients on HIF1α inhibitors being older (70 years vs. 63.9 years). The median CRPC-free survival was longer in men using HIF1α inhibitors compared to those not on inhibitors (6.7 years vs. 2.7 years, P = 0.01) and there was a 71% reduction in the risk of developing CRPC (HR 0.29 [95% CI 0.10–0.78] P = 0.02) after adjustment for Gleason score, age, and prostate-specific antigen (PSA). The median metastasis-free survival in men on HIF1α inhibitors was also significantly longer compared to those on no inhibitors (5.1 years vs. 2.6 years, P = 0.01) with an 81% reduction in the risk of developing metastases (HR 0.19 [CI 0.05–0.76] P = 0.02) after adjustment for Gleason score, age, and PSA. Nonspecific HIF1α inhibitors appear to increase the progression-free survival and reduce the risk of developing CRPC and metastases in patients on continuous ADT.

Highlights

Androgen deprivation therapy (ADT) is a standard treatment for advanced prostate cancer (PC)
We previously demonstrated that the expression of hypoxia-inducible factor 1a (HIF1a) increases the risk of castrate-resistant prostate cancer (CRPC) and metastases in patients on ADT for PC [4], and hypothesized that inhibition of HIF1a may delay or prevent development of these adverse consequences
Drug histories were obtained from the hospital records to identify men being treated with the nonspecific HIF1a inhibitors: digoxin, metformin, and angiotensin-2 receptor blockers (ARB) at the time of starting ADT

Summary

Introduction

Androgen deprivation therapy (ADT) is a standard treatment for advanced prostate cancer (PC). The disease progresses and castrate-resistant prostate cancer (CRPC) develops in a significant proportion of men while on ADT [1]. CRPC is a lethal form of PC that progresses and metastasizes with a median survival of 1–3 years [2]. In some series greater than 84% of CRPC patients have metastases at diagnosis, while a further 33% of patients who do not have metastases at the diagnosis of CRPC may be expected to develop metastases within 2 years [3]. Treatment of CRPC can be difficult as the majority of these tumors become unresponsive to chemotherapy and radiotherapy. Novel therapeutic strategies targeted at delaying or preventing CRPC are of crucial importance in combating this disease

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