CYP17 blockade by abiraterone: further evidence for frequent continued hormone-dependence in castration-resistant prostate cancer

J E Ang, D Olmos, J S de Bono, J E Ang, D Olmos, J S de Bono

Abstract

The limited prognosis of patients with castration-resistant prostate cancer (CRPC) on existing hormonal manipulation therapies calls out for the urgent need for new management strategies. The novel, orally available, small-molecule compound, abiraterone acetate, is undergoing evaluation in early clinical trials and emerging data have shown that the selective, irreversible and continuous inhibition of CYP17 is safe with durable responses in CRPC. Importantly, these efficacy data along with strong preclinical evidence indicate that a significant proportion of CRPC remains dependant on ligand-activated androgen receptor (AR) signalling. Coupled with the use of innovative biological molecular techniques, including the characterisation of circulating tumour cells and ETS gene fusion analyses, we have gained insights into the molecular basis of CRPC. We envision that a better understanding of the mechanisms underlying resistance to abiraterone acetate, as well as the development of validated predictive and intermediate endpoint biomarkers to aid both patient selection and monitor response to treatment, will improve the outcome of CRPC patients.

Figures

Figure 1
Figure 1
Androgen biosynthesis pathway. The physiological effects of abiraterone acetate on steroidogenesis are indicated by arrows next to each steroid precursor. Abiraterone acetate inhibits 17α-hydroxylase (blunt arrow), causing a decline in serum cortisol and a consequent rise in adrenocorticotrophic hormone (ACTH) (broken arrow). This, in turn, results in the rise of deoxycorticosterone and corticosterone by approximately 10- and 40-fold, respectively. The elevated deoxycorticosterone levels result in the expected toxicities of secondary mineralocorticoid syndrome. Abiraterone acetate also inhibits C17,20-lyase (blunt arrow) resulting in significant declines in dehydroepiandrostenedione (DHEA), androstenedione and testosterone. Aldosterone levels fall due to suppression of the renin–angiotensin pathway by high levels of deoxycorticosterone. However, there is a four-fold increase in 11-deoxycortisol, which may be due to the increased ACTH levels driving the partial reversal of the activity of 17α-hydroxylase but not C17,20-lyase.
Figure 2
Figure 2
Chemical structures of abiraterone acetate and abiraterone.

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