Therapeutic targeting steroid sulfatase for advanced prostate cancer

Enzalutamide和阿比特龙对去势抵抗性前列腺癌的治疗最初有效 （CRPC）。然而，对这两种药物的耐药性经常通过不完全解释的机制发生。 明白肿瘤内雄激素生物合成是肿瘤生长的重要机制之一。 去势抵抗性前列腺癌（CRPC）。许多酶参与雄激素的合成，包括 CYP 17 A1和类固醇硫酸酯酶（STS）。在临床治疗中，阿比特龙（Abi）可抑制CYP 17 A1。 然而，阿比特龙对雄激素合成的抑制是不完全的，这表明， CYP 17 A1的添加有助于耐药性。脱氢表雄酮-SO 4（DHEAS）存在于血浆中 前列腺癌患者体内睾酮浓度高达500倍， 在前列腺癌细胞中通过STS转化为脱氢表雄酮，然后转化为雄激素。转化 通过STS将DHEAS循环为DHEA被认为是雄激素的替代来源， 被阿比特龙抑制。因此，STS可能有助于这种持续的雄激素产生，即使在存在 阿比特龙我们的初步数据表明STS在CRPC细胞中过表达。过表达 STS增加细胞生长并赋予对抗雄激素的抗性。此外，我们还发现了几个 新的STS小分子抑制剂，即SI。通过SI靶向STS活性抑制STS活性， 抑制AR转录活性，减少耐药CRPC细胞的生长，并增强 体外和体内Enzalutamide治疗。这些结果表明STS在CRPC中起着关键作用 进展和靶向STS可能是治疗晚期CRPC的可行策略。这一目标 建议是确定STS的作用，并用新的抑制剂靶向这种酶，以提高抗- 雄激素治疗反应。在目标1中，我们将确定STS在耐药性发展中的作用， 恩杂鲁胺。在目标2中，我们将描述CRPC中STS及其类固醇代谢产物的特征，在目标3中，我们将 确定以STS为目标克服治疗抗性的潜力。本建议将STS设置为 下一代抗雄激素治疗进展和耐药的重要机制之一，和 开发新型STS抑制剂，靶向STS活性，以潜在抑制CRPC生长和逆转治疗 阻力

Enzalutamide and abiraterone are initially effective for the treatment of castration-resistant prostate cancer (CRPC). However, resistance to both drugs occurs frequently through mechanisms which are incompletely understood. Intratumoral androgen biosynthesis is well characterized as one of the important mechanisms of castration resistant prostate cancer (CRPC). Many enzymes are involved in androgen synthesis including CYP17A1 and steroid sulfatase (STS). CYP17A1 can be inhibited by abiraterone (Abi) in clinical treatments. However, androgen synthesis inhibition by abiraterone is incomplete, suggesting sustained steroidogenesis in addition to CYP17A1 contributes to resistance. Dehydroepiandrosterone-SO4 (DHEAS) is present at plasma concentrations up to 500 times higher than testosterone in prostate cancer patients and can potentially be converted via STS into desulphated DHEA and then into androgens in prostate cancer cells. Conversion of circulated DHEAS to DHEA by STS is believed to be an alternative source of androgen which cannot be inhibited by abiraterone. Thus, STS may contribute to this sustained androgen production even in the presence of abiraterone. Our preliminary data demonstrates that STS is overexpressed in CRPC cells. Overexpression of STS increases cell growth and confers resistance to anti-androgens. In addition, we have identified several novel small molecule inhibitors of STS, namely, SI. Targeting STS activity by the SI inhibits STS activity, suppresses AR transcriptional activity, reduces the growth of resistant CRPC cells, and enhances enzalutamide treatment in vitro and in vivo. These results suggest that STS plays a critical role in CRPC progression and that targeting STS could be a viable strategy to treat advanced CRPC. The objectives of this proposal are to determining the roles of STS and targeting this enzyme with novel inhibitors to improve anti- androgen treatment response. In aim 1, we will determine the roles of STS in the development of resistance to enzalutamide. In aim 2, we will characterize STS and its steroid metabolites in CRPC, and in aim 3 we will determine the potential of targeting STS to overcome treatment resistance. This proposal will establish STS as one of the important mechanisms of progression and resistance to next-generation anti-androgen therapy, and develop novel STS inhibitors to target STS activity to potentially inhibit CRPC growth and reverse treatment resistance.