Abiraterone Inhibits 3β-Hydroxysteroid Dehydrogenase: A Rationale for Increasing Drug Exposure in Castration-Resistant Prostate Cancer

4645 Background: Treatment with abiraterone acetate (abi) increases the survival of men with castration-resistant prostate cancer (CRPC). Resistance to abi invariably occurs, probably due in part to up-regulation of steroidogenic enzymes and/or other mechanisms that sustain the synthesis of dihydrotestosterone (DHT), which raises the possibility of reversing resistance by concomitant inhibition of other required steroidogenic enzymes. The 1,000 mg daily abi dose was selected for the phase III trials despite the absence of dose-limiting toxicities at higher doses. Based on the 3β-hydroxyl, Δ5-structure, we hypothesized that abi also inhibits 3β-hydroxysteroid dehydrogenase/isomerase (3βHSD), which is absolutely required for the intratumoral synthesis of DHT in CRPC, regardless of origins or routes of synthesis. Methods: We tested if abi inhibits recombinant 3βHSD2 activity in vitro or endogenous 3βHSD activity in LNCaP and LAPC4 cells, including conversion of [3H]-dehydroepiandrosterone (DHEA) to androstenedione (AD), androgen receptor (AR) nuclear translocation, expression of AR-responsive genes, and LAPC4 xenograft growth in orchiectomized mice supplemented with DHEA. Results: Abi has a mixed inhibition pattern of 3βHSD2 in vitro, blocks the conversion from DHEA to AD and DHT with an IC50 of < 1 µM in CRPC cell lines, inhibits AR nuclear translocation and expression of TMPRSS2, and decreases CRPC xenograft growth in DHEA-supplemented mice. Conclusions: Abi blocks 3βHSD enzymatic activity, synthesis of AD and DHT, inhibits the AR-response, and suppresses growth of CRPC cells at concentrations that are clinically achievable. Variable abi inhibition of 3βHSD might account in part for the heterogeneous clinical response to abi. More importantly, 3βHSD inhibition with abi might be clinically harnessed to reverse resistance to CYP17A1 inhibition at the standard dose by dose-escalation, or simply by administration with food to increase drug exposure.

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Inhibition of 3β-hydroxysteroid dehydrogenase by abiraterone as a rationale for dose escalation in castration-resistant prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.5_suppl.209 ◽

2012 ◽

Vol 30 (5_suppl) ◽

pp. 209-209

Author(s):

Nima Sharifi ◽

Rui Li ◽

Kristen Evaul ◽

Kamalesh Sharma ◽

Richard J Auchus

Keyword(s):

Prostate Cancer ◽

Dose Escalation ◽

Nuclear Translocation ◽

Hydroxysteroid Dehydrogenase ◽

Phase Iii ◽

Castration Resistant Prostate Cancer ◽

Steroidogenic Enzymes ◽

Xenograft Growth ◽

Castration Resistant

209 Background: Treatment with abiraterone acetate (abi) increases the survival of men with castration-resistant prostate cancer (CRPC). Resistance to abi invariably occurs, probably due in part to up-regulation of steroidogenic enzymes and/or other mechanisms that sustain the synthesis of dihydrotestosterone (DHT), which raises the possibility of reversing resistance by concomitant inhibition of other required steroidogenic enzymes. The 1000 mg daily abi dose was selected for the phase III trials despite the absence of dose-limiting toxicities at higher doses. Based on the 3β-hydroxyl, Δ5-structure, we hypothesized that abi also inhibits 3β-hydroxysteroid dehydrogenase/isomerase (3βHSD), which is absolutely required for the intratumoral synthesis of DHT in CRPC, regardless of origins or routes of synthesis. Methods: We tested if abi inhibits recombinant 3βHSD2 activity in vitro or endogenous 3βHSD activity in LNCaP and LAPC4 cells, including conversion of [3H]-dehydroepiandrosterone (DHEA) to androstenedione (AD), androgen receptor (AR) nuclear translocation, expression of AR-responsive genes, and LAPC4 xenograft growth in orchiectomized mice supplemented with DHEA. Results: Abi has a mixed inhibition pattern of 3βHSD2 in vitro, blocks the conversion from DHEA to AD and DHT with an IC50 of < 1 µM in CRPC cell lines, inhibits AR nuclear translocation and expression of TMPRSS2, and decreases CRPC xenograft growth in DHEA-supplemented mice. Conclusions: Abi blocks 3βHSD enzymatic activity, synthesis of AD and DHT, inhibits the AR-response, and suppresses growth of CRPC cells at concentrations that are clinically achievable. Variable abi inhibition of 3βHSD might account in part for the heterogeneous clinical response to abi. More importantly, 3βHSD inhibition with abi might be clinically harnessed to reverse resistance to CYP17A1 inhibition at the standard dose by dose-escalation, or simply by administration with food to increase drug exposure.

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Abstract 1413: Exploring the prognostic value of microRNAs and drug exposure in patients with metastatic castration resistant prostate cancer treated with abiraterone: a prospective observational study

10.1158/1538-7445.am2020-1413 ◽

2020 ◽

Author(s):

Emmy Boerrigter ◽

Guillemette E. Benoist ◽

Inge M. van Oort ◽

Gerald W. Verhaegh ◽

Onno van Hooij ◽

...

Keyword(s):

Prostate Cancer ◽

Observational Study ◽

Prognostic Value ◽

Prospective Observational Study ◽

Drug Exposure ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant

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3β-Hydroxysteroid Dehydrogenase Is a Possible Pharmacological Target in the Treatment of Castration-Resistant Prostate Cancer

Endocrinology ◽

10.1210/en.2010-0138 ◽

2010 ◽

Vol 151 (8) ◽

pp. 3514-3520 ◽

Cited By ~ 50

Author(s):

Kristen Evaul ◽

Rui Li ◽

Mahboubeh Papari-Zareei ◽

Richard J. Auchus ◽

Nima Sharifi

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Androgen Receptor ◽

Nuclear Translocation ◽

De Novo ◽

Hydroxysteroid Dehydrogenase ◽

Adrenal Steroids ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Pharmacological Target

Prostate cancer usually responds to androgen deprivation therapy, although the response in metastatic disease is almost always transient and tumors eventually progress as castration-resistant prostate cancer (CRPC). CRPC continues to be driven by testosterone or dihydrotestosterone from intratumoral metabolism of 19-carbon adrenal steroids from circulation, and/or de novo intratumoral steroidogenesis. Both mechanisms require 3β-hydroxysteroid dehydrogenase (3βHSD) metabolism of Δ5-steroids, including dehydroepiandrosterone (DHEA) and Δ5-androstenediol (A5diol), to testosterone. In contrast, reports that DHEA and A5diol directly activate the androgen receptor (AR) suggest that 3βHSD metabolism is not required and that 3βHSD inhibitors would be ineffective in the treatment of CRPC. We hypothesized that activation of AR in prostate cancer by DHEA and A5diol requires their conversion via 3βHSD to androstenedione and testosterone, respectively. Here, we show that DHEA and A5diol induce AR chromatin occupancy and AR-regulated genes. Furthermore, we show that Δ5-androgens undergo 3β-dehydrogenation in prostate cancer and that induction of AR nuclear translocation, AR chromatin occupancy, transcription of PSA, TMPRSS2, and FKBP5, as well as cell proliferation by DHEA and A5diol, are all blocked by inhibitors of 3βHSD. These findings demonstrate that DHEA and A5diol must be metabolized by 3βHSD to activate AR in these models of CRPC. Furthermore, this work suggests that 3βHSD may be exploited as a pharmacologic target in the treatment of CRPC.

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