Therapeutic targeting steroid sulfatase for advanced prostate cancer

类固醇硫酸酯酶靶向治疗晚期前列腺癌

基本信息

批准号：
10057773
负责人：
Allen C Gao
金额：
$ 38.72万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10057773
关键词：
Anabolism Androgen Antagonists Androgen Receptor Androgens Antiandrogen Therapy Biological Availability CYP17A1 gene Cancer Patient Cell Line Cells Clinical Clinical Treatment Data Databases Down-Regulation Enzymes Generations Genetic Transcription Growth Hydroxysteroid Dehydrogenases In Vitro Intervention Investigation LNCaP Malignant neoplasm of prostate Mediating Messenger RNA Modeling Mutation Organic Anion Transporters Oxidoreductase Pharmaceutical Preparations Plasma Play Production Resistance Resistance development Role Safety Sampling Signal Transduction Small Interfering RNA Source Specimen Stanolone Steroid biosynthesis Steroids Sulfatases System Testing Testosterone Time Treatment Failure VCaP Variant Xenograft procedure abiraterone advanced prostate cancer androgen deprivation therapy androgenic carcinogenesis castration resistant prostate cancer cell growth dehydroepiandrosterone design effective therapy experience improved in vivo in vivo Model inhibitor/antagonist intratumoral androgen knock-down men next generation novel overexpression prostate cancer cell prostate cancer progression small molecule inhibitor therapeutic target therapy resistant treatment response treatment strategy

项目摘要

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.

恩扎拉胺和阿比特龙最初对治疗持cast割前列腺癌的治疗有效（CRPC）。但是，对这两种药物的抗性经常通过不完全的机制发生理解。肿瘤内雄激素生物合成被很好地描述为一种重要机制之一抑制前列腺癌（CRPC）。许多酶参与雄激素合成，包括 CYP17A1和类固醇硫酸酶（STS）。 Abiraterone（ABI）可以在临床治疗中抑制CYP17A1。然而，阿迪特龙抑制雄激素的合成是不完整的，这表明持续的类固醇生成除了CYP17A1外，还有助于抵抗力。血浆中存在脱氢双足酮-SO4（DHEAS）在前列腺癌患者中，浓度比睾丸激素高500倍，可能是通过STS转化为脱硫DHEA，然后在前列腺癌细胞中转化为雄激素。转换据信，通过STS向DHEA循环DHEA是雄激素的替代来源被阿比罗酮抑制。因此，即使在存在的情况下，STS也可能导致这种持续的雄激素产生阿比罗酮。我们的初步数据表明，STS在CRPC细胞中过表达。过表达 STS增加了细胞的生长，并赋予对抗雄激素的抗性。此外，我们已经确定了几个 STS的新型小分子抑制剂，即Si。 SI靶向STS活性抑制STS活性，抑制AR转录活性，减少耐药性CRPC细胞的生长，并增强 enzalutamide在体外和体内处理。这些结果表明STS在CRPC中起关键作用进展和靶向STS可能是治疗先进CRPC的可行策略。目标的目标建议是确定STS的作用，并用新型抑制剂靶向这种酶，以改善抗抗雄激素治疗反应。在AIM 1中，我们将确定STS在抗性发展中的作用恩扎拉胺。在AIM 2中，我们将在CRPC中表征STS及其类固醇代谢物，在AIM 3中，我们将确定靶向STS克服治疗抗性的潜力。该建议将建立STS 进展和对下一代抗雄激素治疗的重要机制之一，以及开发新型的ST抑制剂以靶向STS活性以潜在地抑制CRPC生长并逆转处理反抗。