We agree with the letter by Mostaghel et al. and their previous publications about the contribution of intratumoral androgens in the evolution of castration-resistant prostate cancer (CRPC). The efficacy of new compounds targeting steroidogenesis has been shown in recent phase II clinical trials in CRPC patients (1, 2), raising the interest of the intratumoral presence of mechanisms that produce androgens after androgen deprivation therapy (ADT) as a potential treatment target. Although multicenter clinical phase III trials with these compounds are still pending, suppression of intratumoral androgen levels seems to be a promising treatment strategy for CRPC.
The presence of intratumoral androgens after ADT has been firmly established. Possible causes include intracrine conversion of precursor steroids derived from the adrenal cortex and de novo steroidogenesis from cholesterol. Reports by the letter's authors (3, 4), ourselves (5), and others have shown intratumoral expression of steroidogenic enzyme mRNAs or proteins in a subset of cell lines, xenografts, and patient samples. We agree with Mostaghel et al. that intratumoral de novo steroidogenesis could occur in a small subset of patients. Indeed, androgen synthesis from cholesterol by LNCaP and CRPC cells was shown in an elegant way (4). The relevance of these studies in cell line and xenograft models, however, should be interpreted with caution because adrenal androstenedione, present in nanomolar quantities in serum of CRPC patients, is absent in charcoal-treated and (castrate) murine serum (6).
Our published data of patient samples indicate that a minority of samples express those enzymes critical for de novo steroidogenesis at low levels (5). Indeed, metastatic CRPC samples were not included in our sample set; we are currently working on sampling of these essential patient tissues. The location of our primers did not influence the levels of expression detected; the addition of random hexamers to the reverse transcriptase reaction did not alter sample threshold levels compared with oligo(dT) alone (unpublished data). In addition, we did not detect upregulation of steroidogenic enzyme mRNAs in CRPC patient samples, with the exception of AKR1C3. The heat map shown by Mostaghel et al. in Fig. 1B also points toward increased AKR1C3 expression in the majority of CRPC samples. De novo steroidogenesis requires concurrent positive expression of both CYP17A1 and HSD3B1. This was only shown in 5 of 19 CRPC samples in our study and in 7 of 24 CRPC samples according to Fig. 1B. The expression of CYP17 protein in localized and metastatic patient tissue is nicely shown in Fig. 1A, but is only relevant if HSD3B1 and androgen receptor expression levels are also significant.
The relative contributions of adrenal versus intratumoral de novo androgen production to CRPC progression have yet to be determined and are subject to ongoing investigations. In the phase II abiraterone acetate trial (1), however, clinical response, measured as a prostate-specific antigen decline of ≥50%, was associated with pretreatment serum levels of androstenedione, dehydroepiandrosterone (DHEA), and DHEA sulfate. These first clinical findings thus imply that successful antitumor effects through CYP17 inhibition have been achieved in those patients with the highest serum levels of adrenal androgens.
Importantly, new compounds targeting steroidogenesis will prevent androgen production regardless of its endogenous source. The efficacy of these compounds seems promising and requires further study. Further elaboration of the source of intratumoral androgens could aid in finding those patients expected to respond most favorably to inhibition of steroidogenesis. The first data indicate serum adrenocortical steroid levels as potential markers for treatment success. Future studies with large sets of (metastatic) CRPC samples will be necessary to determine the contribution of de novo intratumoral steroidogenesis and other factors. These investigations as well as the upcoming phase III clinical trials with steroidogenic enzyme inhibitors form exciting developments in the field and will presumably have significant effect on new treatment strategies for CRPC patients.
See the original Letter to the Editor, p. 8247.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.