Elucidating a novel metabolic mechanism of glucosamine-driven treatment resistance in castration-resistant prostate cancer through stimulation of 3b-HSD1-mediated DHEA metabolism

通过刺激 3b-HSD1 介导的 DHEA 代谢，阐明去势抵抗性前列腺癌中葡萄糖胺驱动的治疗抵抗的新代谢机制

• 批准号: 10387549
• 负责人: Shelley Valle
• 金额: $ 6.13万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2023-04-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10387549
• 关键词: Adrenal Glands; Affect; Androgen Metabolism; Androgens; Antiandrogen Therapy; Binding; Biology; Cancer Biology; Cancer Patient; Cessation of life; Chronic; Clinic; Clinical; Co-Immunoprecipitations; Communication; Communication Programs; Complex; Data; Development; Development Plans; Diabetes Mellitus; Disease; Educational process of instructing; Educational workshop; Enzymes; Fellowship; Fibrinogen; Fibroblasts; Genes; Genetic Transcription; Glucosamine; Growth; Hexosamines; High Fat Diet; Hormonal; Human; Hydroxysteroid Dehydrogenases; Hypogonadism; In Vitro; Institutes; Insulin Resistance; Knock-out; Knowledge; Leadership; Malignant Neoplasms; Malignant neoplasm of prostate; Mass Spectrum Analysis; Measures; Mediating; Metabolic; Metabolic dysfunction; Metabolic syndrome; Metabolism; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Pathway interactions; Patient Care; Patients; Play; Post-Translational Protein Processing; Prostate Cancer therapy; Proteins; Proteomics; Research; Research Institute; Resistance; Resistance development; Role; Sampling; Science; Scientist; Serum; Signal Transduction; Signaling Molecule; Skin Cancer; Steroids; Testing; Testosterone; Therapeutic; Training; Translational Research; United States; Uridine Diphosphate; Variant; Work; Xenograft procedure; advanced prostate cancer; androgen deprivation therapy; anticancer research; base; career development; castration resistant prostate cancer; clinically relevant; cohort; combat; dehydroepiandrosterone; experience; hormone therapy; improved; in vivo; innovation; men; metabolomics; novel; predict clinical outcome; predicting response; predictive marker; promoter; prospective; prostate cancer cell; prostate cancer progression; resistance mechanism; response; response biomarker; skills; sugar; therapy resistant; transcription factor; treatment strategy; tumor; tumor microenvironment; tumor xenograft; undergraduate student

SUMMARY Prostate cancer (PCa) is the most common cancer among men in the United States, with an estimated 191,930 new cases in 2020 and 33,330 deaths. PCa progression depends primarily on androgen signaling, and thus androgen deprivation therapy (ADT) is the first-line treatment for advanced PCa. Acquired resistance to ADT and progression to castration-resistant prostate cancer (CRPC) occurs in nearly all patients, in part due to continued androgen synthesis from extragonadal precursor steroids. 3β-hydroxysteroid dehydrogenase-1 (3β-HSD1) is the first enzyme responsible for metabolizing the adrenal androgen, DHEA, to more potent downstream androgens, and has been demonstrated to play a critical role in CRPC. Our preliminary studies identified glucosamine as having a role in enhancing 3β-HSD1 enzymatic activity in PCa cells. I propose to investigate a novel metabolic mechanism of glucosamine-driven treatment resistance in castration-resistant prostate cancer through stimulation of 3β-HSD1-mediated DHEA metabolism. Altered glucosamine metabolism, including enhanced downstream O-GlcNAcylation, has been demonstrated to occur in the metabolic dysfunction of Type 2 diabetes (T2D). Associations between T2D and outcomes in PCa have been long recognized, but the underlying mechanisms are not clearly defined. Further, hormonal treatment itself results in metabolic syndrome in > 50% of treated men. I hypothesize that the metabolic syndrome that occurs as a consequence of ADT results in elevated glucosamine that can ultimately drive treatment resistance through effects on 3β-HSD1 and androgen metabolism. Aim 1 will delineate the mechanism by which glucosamine enhances 3β-HSD1 transcription and enzymatic activity. Aim 2 will interrogate the role of glucosamine in 3β-HSD1-mediated DHEA metabolism and CRPC development in vivo. Aim 3 will assess the clinical relevance of glucosamine-mediated increased androgen metabolism in PCa progression, including its role in mediating responses to hormonal therapy. The findings of this project have the potential to inform comprehensive therapeutic strategies in the treatment of CRPC that take into consideration ameliorating or targeting the metabolic disturbances of ADT. This work will be conducted at the Lerner Research Institute at Cleveland Clinic in the lab of Dr. Nima Sharifi. Through completion of this project, I will expand my knowledge and skills in prostate cancer biology and translational research. Coursework and workshops on these topics will supplement my research-based training. As part of my career development plan, I will also work to improve my science communication skills and gain leadership experience through regular presentations, taking part in our institute's science communication program, teaching an undergraduate biology course, and serving on our postdoctoral association committee. I am confident that through completion of this fellowship, I will make a significant contribution to the field of prostate cancer research, will successfully transition into a role as an independent scientist, and will go on significantly influence the field and patient care.

总结 前列腺癌（PCa）是美国男性中最常见的癌症，估计 2020年新增病例191,930例，死亡33,330例。前列腺癌的进展主要取决于雄激素信号传导， 因此雄激素剥夺疗法（ADT）是晚期PCa的一线治疗。获得性抗性 几乎所有患者都发生ADT和进展为去势抵抗性前列腺癌（CRPC），部分原因是 持续从性腺外前体类固醇合成雄激素3β-羟类固醇脱氢酶-1 （3β-HSD 1）是负责代谢肾上腺雄激素DHEA的第一种酶， 下游雄激素，并已被证明在CRPC中发挥关键作用。我们的初步研究 鉴定葡糖胺在PCa细胞中具有增强3β-HSD 1酶活性的作用。我建议 探讨葡萄糖胺驱动去势抵抗者治疗抵抗新代谢机制 前列腺癌通过刺激3β-HSD 1介导的DHEA代谢。葡萄糖胺改变 已经证明，代谢，包括增强的下游O-GlcNAc酰化，发生在 2型糖尿病（T2 D）的代谢功能障碍。T2 D与PCa结局之间的相关性已被 这一点早已得到承认，但其内在机制尚未明确界定。此外，激素治疗本身 在> 50%的治疗男性中导致代谢综合征。我假设代谢综合征 ADT导致葡萄糖胺升高，最终导致治疗耐药性 通过影响3β-HSD 1和雄激素代谢。目标1将描述 葡糖胺增强3β-HSD 1转录和酶活性。目标2将询问 葡糖胺在3β-HSD 1介导的DHEA代谢和体内CRPC发展中的作用。目标3将评估 葡糖胺介导的雄激素代谢增加与前列腺癌进展的临床相关性，包括其 在调节激素治疗反应中的作用。该项目的调查结果有可能为 在CRPC的治疗中，考虑到改善或 针对ADT的代谢紊乱。这项工作将在勒纳研究所进行， Nima Sharifi博士实验室的克利夫兰诊所。通过完成这个项目，我将扩大我的知识面 以及前列腺癌生物学和转化研究方面的技能。关于这些主题的课程和讲习班 将补充我的研究训练作为我职业发展计划的一部分， 我的科学沟通技巧，并通过定期演讲获得领导经验，参加 我们研究所的科学传播计划，教本科生物学课程，并在我们的服务 博士后协会委员会。我相信，通过完成这项奖学金，我将使一个 对前列腺癌研究领域的重大贡献，将成功地过渡到一个角色， 独立的科学家，并将继续显着影响该领域和病人护理。