The effects of non-specific HIF1α inhibitors on development of castrate resistance and metastases in prostate cancer — YRD
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The effects of non-specific HIF1α inhibitors on development of castrate resistance and metastases in prostate cancer (#119)

Weranja Ranasinghe 1 2 3 , Shomik Sengupta 1 , Scott Williams 3 , Mike Chang 1 , Arthur Shulkes 1 , Damien M Bolton 1 , Graham Baldwin 1 , Oneel Patel 1
  1. Royal Melbourne Hospital/North-East Health, Wangaratta, Australia
  2. Department of Urology, Austin Health/ University of Melbourne, Melbourne
  3. Peter MacCullum Cancer Institute, Melbourne

Introduction

We have previously demonstrated that the expression of HIF1α increases the risk of castrate-resistance (CRPC) and metastases in patients on androgen deprivation therapy (ADT) for prostate cancer (PCa)[1].

Digoxin, metformin and angiotensin-2 inhibitors have all been shown to inhibit HIF1α.

Objectives

We investigated the effects of these non-specific HIF1α inhibitors on development of CRPC and metastases.

Methods

A review of prospectively collected medical records was conducted of all men who had continuous ADT as first line therapy and received chemotherapy for CRPC 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 Cox-proportional hazard regression were used.

Results

Ninety-eight patients meeting the criteria were identified. 20 patients (20.4%) were treated with the non-specific HIF1α inhibitors. Both groups had similar Gleason scores (8) and patients on HIF1α inhibitors were older (68.9 yrs vs 64.6 yrs).

The median time for developing CRPC in patients not on HIF1α inhibitors was 2.8 years compared to 6.8 years in patients using HIF1α inhibitors (log rank test p=0.01). On a multivariate regression analysis adjusting for Gleason score and age, there was 68% reduction [HR 0.32 (CI 0.12 – 0.85) p=0.02] in the risk of developing CRPC in patients who were on HIF1α inhibitors.

The median metastases free survival time in men on HIF1α inhibitors was significantly longer than the those not on inhibitors (5.1 yrs vs. 2.6 yrs, p=0.01) and there was a 76% reduction in the risk of developing metastases in men on HIF1α inhibitors (HR 0.24 (CI 0.07 – 0.81) p=0.03]. 

Conclusions

Non-specific HIF1α inhibitors are likely to increase the progression free survival and reduce the risk of developing CRPC and metastases in patients on continuous ADT. Larger prospective studies are warranted to confirm these findings.1  

  1. Weranja Kalana Bodhisiri Ranasinghe LX, Suzana Kovac, Mike Chang, Arthur Shulkes, Damien M Bolton, Graham Baldwin, Oneel Patel. Hypoxia-inducible factor 1α: A screening tool for predicting development of castrate resistant prostate cancer. Asco Abstracts 2012: e15117, J Clin Oncol 30, 2012 (suppl; abstr e15117) [serial on the Internet]. Available from: http://abstract.asco.org/AbstView_114_93368.html.