Therapeutic targeting steroid sulfatase for advanced prostate cancer

苯扎鲁胺和阿比特龙对耐去势前列腺癌的治疗初步有效 (CRPC)。然而，对这两种药物的耐药性经常是通过不完全的机制发生的。 明白了。肿瘤内雄激素的生物合成是肿瘤发生的重要机制之一。 耐去势前列腺癌(CRPC)。许多酶参与雄激素的合成，包括 CyP17A1和类固醇硫酸酯酶(STS)。阿比特龙(Abi)在临床治疗中可抑制细胞色素P17A1的表达。 然而，阿比特龙对雄激素合成的抑制是不完全的，这表明在 此外，细胞色素P17A1基因也会产生抗性。脱氢表雄酮-硫酸(DHEAS)存在于血浆中 前列腺癌患者体内的睾酮浓度高达睾酮的500倍，可能是 通过STS转化为脱硫型脱氢表雄酮，然后在前列腺癌细胞中转化为雄激素。转换为 STS将DHEAS循环到DHEA被认为是雄激素的替代来源，而雄激素不能 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，即使在存在的情况下 阿比特龙。我们的初步数据表明，STS在CRPC细胞中过表达。过度表达 STS可促进细胞生长并对抗雄激素产生抵抗力。此外，我们还确定了几个 新型STS小分子抑制剂，即SI。SI以STS活性为靶标抑制STS活性， 抑制AR转录活性，减少耐药的CRPC细胞的生长，并增强 苯扎鲁胺的体内外治疗。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。这样做的目的是 建议确定STS的作用并使用新的抑制剂靶向该酶以提高抗肿瘤活性 雄激素治疗反应。在目标1中，我们将确定STS在抗药性发展中的作用 苯扎鲁胺。在目标2中，我们将表征STS及其在CRPC中的类固醇代谢物，在目标3中，我们将 确定靶向STS以克服治疗耐药性的潜力。这项提案将把STS建立为 下一代抗雄激素治疗进展和耐药的重要机制之一，以及 开发新型STS抑制剂，靶向STS活性，潜在地抑制CRPC生长和逆转治疗 抵抗。

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.