br Targeting metabolism of DHEAS to DHEA with STS
Targeting metabolism of DHEAS to DHEA with STS inhibitors, such
as STX64, has been proposed as a new approach to treat sex hormone-related cancers, including breast cancer and PCa, and have been tested in phase I and phase II clinical trials (Woo et al., 2011; Williams, 2013; Day et al., 2009; McNamara et al., 2013). A phase I trial with STX64 demonstrated promising results as indicated by induction of stable disease in breast cancer patients (Stanway et al., 2006; Coombes et al., 2013). A phase II trial following chemotherapy of post-menopausal endometrial cancer patients was discontinued due to a lack of beneficial eﬀects (Ipsen, 2013). Results of other trials on STX64 in patients with breast cancer or PCa were summarized by McNamara KM et al. (McNamara et al., 2013). In the present study, the STS inhibitor STX64 blocked DHT production from DHEAS, diminished AR activity and in-hibited growth stimulation by DHEAS. The results suggest that con-version of the highly available DHEAS to DHEA, thereby raising the eﬀective intracellular concentration of DHEA, is required to produce bioactive levels of DHEA. The eﬃciency of DHEAS to DHEA conversion, and DHEA or DHEAS to DHT conversion require further investigation using more accurate assessment of androgens such as mass spectro-metry. Additionally, since Dynasore may rely on transporters for DHEAS uptake (Roth et al., 2012; Obaidat et al., 2012; Cho et al., 2014), whether and how DHEAS uptake transporters may contribute to the utility of DHEAS by PCa cells need to be studied. In patients treated with castration or abiraterone, circulating levels of DHEAS remained in the μM range, whereas, circulating DHEA was diminished to con-centrations below nM (Snaterse et al., 2017). Consequently, targeting the metabolic conversion of DHEAS to DHEA with STS inhibitors re-present a logical adjuvant therapy in combination with ADT or abir-aterone treatment.
Prostatic tissue concentrations of DHEA and DHEAS based on pub-lished results are 20 nM and 40 nM, respectively (Wurzel et al., 2007; Ryan et al., 2007; Nishiyama et al., 2007; Mostaghel et al., 2007; Litman et al., 2006; Page et al., 2006; Mohler et al., 2004a,b). The prostate tissue concentration of DHEA is higher than in circulation, whereas, the intra-prostatic level of DHEAS is much lower than in cir-culation. The tissue levels of DHEAS and DHEA presumably represent an equilibrium that results from continuing uptake from the circulation, metabolic conversion of DHEAS to DHEA and conjugation/excretion of DHT. Consequently, it is not clear whether, and how much, DHT may be produced from DHEA or DHEAS in prostate tissue continuously exposed to adrenal androgens. The ex vivo and in vitro experiments in the present study were performed over a short time period, and in a closed system.
Since the ex vivo system is closed, it will allow in future studies the analysis of all products of metabolism, including conjugates, which would be almost impossible to do in vivo. On the other hand, growth of VCaP xenografts was maintained in castrated mice that were treated with DHEA, and the serum concentration of DHEA in DHEA-treated mice was 16.5 nM and 24.7 nM in SCID mice and nude mice, respec-tively (Supplementary Data Fig S3), similar to the physiological circu-lating concentration in human. This result suggests that long-term ex-posure to DHEA may be beneficial to PCa cells. Nevertheless, the data demonstrate that prostate tissue is equipped with eﬀective metabolic capacity to produce DHT using adrenal androgens. Therefore, this capability should not be neglected, while better targeting approaches are needed to fully block the capacity of using adrenal androgens.
There are at least two circumstances under which PCa cells may be exposed directly to the μM level of DHEAS present in the circulation. One is when PCa cells are actually in the circulation during metastasis. The other is when locally advanced PCa is treated with ADT. The prostatic endothelium undergoes apoptotic cell death, leading to acute de-endothelialization after ADT (Godoy et al., 2011). The loss of the selectively permeable endothelial cell-mediated blood-tissue barrier may expose PCa cells to circulating levels of DHEAS.
In summary, the results of the present studies demonstrate the po-tential of prostate tissue, and PCa cells to metabolize adrenal androgens for DHT production. Although DHEA may be preferred over DHEAS by PCa cells, only DHEAS is available for DHT production at physiologi-cally relevant concentrations. Therefore, there is place for STS in-hibitors in PCa treatment. Abiraterone is used to treat CRPC and re-duces eﬀectively the serum DHEAS and DHEA to 0.14–0.4 μM and 0.08–2.7 nM, respectively (Snaterse et al., 2017; McKay et al., 2017; Attard et al., 2008; Taplin et al., 2014). Although the significance of the residual serum DHEAS and DHEA in intratumoral T and DHT synthesis needs further investigations, blocking of DHEAS and DHEA for DHT synthesis may facilitate complete ADT.