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Deciphering microbial contribution to androgen bioavailability in castration resistant prostate cancer patients

破译微生物对去势抵抗性前列腺癌患者雄激素生物利用度的贡献

基本信息

批准号：
10573918
负责人：
Raad Gharaibeh
金额：
$ 20.79万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10573918
关键词：
Algorithms Anabolism Androgen Metabolism Androgens Bacteria Bacterial Genes Bacteroides Beta-glucuronidase Bile fluid Bioinformatics Biological Availability Bioreactors CYP17A1 gene Cancer Etiology Cancer Patient Castrate sensitive prostate cancer Cessation of life Clinical Clostridium Development Disease Enzymes Evaluation Feces Foundations Future Genes Genomics Human Hydrocortisone Interdisciplinary Study Intervention Intestines Knowledge Liver MALDI-TOF Mass Spectrometry Malignant Neoplasms Malignant neoplasm of prostate Metabolic Biotransformation Mus Operon Orchiectomy Organism Outcome Patients Play Pre-Clinical Model Prevention strategy Production Prognosis Prostate Cancer therapy Research Resistance Resistance development Role Route Ruminococcus Science Serum Shotguns Source Steroids System Talents Testing Testosterone United States Work absorption advanced prostate cancer androgen biosynthesis androgen deprivation therapy cancer diagnosis castration resistant prostate cancer cohort deprivation drug efficacy drug metabolism enzyme biosynthesis gut bacteria gut microbiome gut microbiota human male inhibitor innovation men metabolomics metagenome microbial microbial genomics microbiome microorganism novel novel strategies prevent prostate cancer prevention prostate cancer progression testosterone biosynthesis treatment response treatment strategy tumor vpr Genes whole genome

项目摘要

PROJECT SUMMARY An emerging role of microbiome in cancer is the capacity of microorganisms to impact treatment, drug efficacy and metabolism. For example, we recently showed that the gut microbiome plays an important role in castration resistant prostate cancer (CRPC) through microbial-derived androgen synthesis (Pernigoni et al. Science. 2021;374(6564):216-224). In that study, we found that androgen deprivation in both mice and humans promotes the expansion of specific gut bacteria capable of converting testosterone precursors into active testosterone, through bacterial CYP17A1-like enzymes (Ruminococcus gnavus, Ruminococcus sp. and Bacteroides acidifaciens), thus increasing its levels in patients and mice with CRPC and preventing complete suppression of testosterone during androgen deprivation therapy. In addition to the biosynthetic route, testosterone bioavailability could represent an additional means to regulate therapeutic responses. Androgens are glucuronidated in the liver for elimination and a fraction of these glucuronidated androgens reaches the gut through the bile and are targeted by bacterial β-glucuronidases (GUS) (Ruminococcus gnavus, Ruminococcus sp., Bacteroides acidifaciens and Clostridium scindens) for “reactivation” and potentially reabsorption. In fact, androgen concentration is higher in the intestine than in serum of human males. Another route by which gut microbiota contribute to the bioavailability of androgens is through cortisol to 11β-Hydroxyandrostenedione conversion by bacterial steroid-17,20-desmolases (Clostridium scindens desABCD operon). In turn, 11β- Hydroxyandrostenedione is converted to 11-oxyandrogen, which contribute to the tumor androgen pool. It is unclear how much each of these different routes contribute to the pool of circulating androgens. Our central hypothesis is that gut microbiome contributes to the production and bioavailability of androgens through a combination of biosynthetic and bioavailability routes. The objective of this project is to computationally identify androgen-related bacterial enzymes (CYP17A1-like, GUS, desA and desB) in CRPC patients gut microbiome and to isolate bacterial species harboring those enzymes for functional analysis. The rationale for the proposed research is that the outcomes will provide targets for future development and evaluation of interventions in CRPC patients that minimize or prevent the bioavailability of androgens. Our hypothesis will be tested through two specific aims: Aim 1) Identify androgen-related bacterial enzymes in the gut microbiome of prostate cancer patients. Aim 2) Functional characterization of bacterial species possessing androgen-related enzymes. At completion, this project will identify bacterial enzymes involved in androgen biotransformation and biosynthesis and obtain bacterial species harboring these enzymes. This knowledge will serve as a springboard for future functional studies using preclinical models of CRPC and inhibitors targeting bacterial androgen biotransformation and synthesis enzymes and/or species that harbor them to alleviate CRPC, thus providing an innovative approach to slow or prevent prostate cancer progression.

项目概要微生物组在癌症中的一个新兴作用是微生物影响治疗、药物疗效的能力和新陈代谢。例如，我们最近表明肠道微生物组在去势中发挥着重要作用通过微生物源性雄激素合成来治疗耐药性前列腺癌 (CRPC)（Pernigoni 等人，Science。 2021；374(6564):216-224)。在那项研究中，我们发现小鼠和人类的雄激素剥夺都会促进特定肠道细菌的扩增能够将睾酮前体转化为活性睾酮，通过细菌 CYP17A1 样酶（瘤胃球菌、瘤胃球菌和拟杆菌 Acidifaciens），从而增加 CRPC 患者和小鼠体内的水平，并防止完全抑制雄激素剥夺治疗期间的睾酮。除了生物合成途径外，睾酮生物利用度可以代表调节治疗反应的另一种手段。雄激素是在肝脏中进行葡萄糖醛酸化以消除，这些葡萄糖醛酸化雄激素的一部分到达肠道通过胆汁，并被细菌 β-葡萄糖醛酸酶 (GUS)（颚状瘤胃球菌、瘤胃球菌 sp.、Bacteroides Acidifaciens 和 Clostridium scindens）用于“重新激活”和潜在的重吸收。实际上，人类男性肠道中的雄激素浓度高于血清中的雄激素浓度。肠道的另一条途径微生物群通过皮质醇转化为 11β-羟基雄烯二酮，从而提高雄激素的生物利用度通过细菌类固醇-17,20-去氨酶（Clostridium scindens desABCD 操纵子）进行转化。反过来，11β- 羟基雄烯二酮转化为 11-氧雄激素，这有助于肿瘤雄激素库。这是目前还不清楚这些不同途径对循环雄激素库的贡献有多大。我们的中央假设肠道微生物组通过以下方式促进雄激素的产生和生物利用度：生物合成和生物利用度途径的结合。该项目的目标是通过计算确定 CRPC 患者肠道微生物组中雄激素相关细菌酶（CYP17A1 样、GUS、desA 和 desB）并分离含有这些酶的细菌物种进行功能分析。拟议的理由研究结果将为 CRPC 干预措施的未来开发和评估提供目标最大限度地减少或阻止雄激素生物利用度的患者。我们的假设将通过两个方面进行检验具体目标：目标 1) 鉴定前列腺癌肠道微生物组中与雄激素相关的细菌酶患者。目标 2) 具有雄激素相关酶的细菌物种的功能表征。在完成后，该项目将鉴定参与雄激素生物转化和生物合成的细菌酶并获得含有这些酶的细菌物种。这些知识将成为未来的跳板使用 CRPC 和针对细菌雄激素生物转化的抑制剂的临床前模型进行功能研究以及合成酶和/或含有它们的物种来缓解 CRPC，从而提供了一种创新的方法减缓或预防前列腺癌进展的方法。