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

摘要 前列腺癌(PCA)是美国男性中最常见的癌症，据估计 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， 因此，雄激素剥夺疗法(ADT)是晚期前列腺癌的一线治疗方法。获得性抗性 ADT和进展为去势抵抗前列腺癌(CRPC)几乎在所有患者中都会发生，部分原因是 从性腺外前体类固醇继续合成雄激素。3β-羟基类固醇脱氢酶-1 (3β-hsd1)是第一种负责将肾上腺雄激素dhea代谢到更有效的酶。 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 确定氨基葡萄糖在前列腺癌细胞中具有增强3β-HSD1酶活性的作用。我提议 探讨氨基葡萄糖抗去势治疗抗性的代谢新机制 前列腺癌通过刺激3-β-HSD1介导的脱氢表雄酮代谢。改性氨基葡萄糖 新陈代谢，包括下游增强的O-GlcN酰化，已被证明发生在 2型糖尿病代谢功能障碍(T2D)。在PCa中，T2D和结果之间的关联是 人们早就认识到了这一点，但其潜在机制并未得到明确界定。此外，荷尔蒙治疗本身 结果50%的接受治疗的男性出现代谢综合征。我假设代谢综合征 由于ADT导致氨基葡萄糖升高，最终会导致治疗耐药 通过对3-β-HSD1和雄激素代谢的影响。目标1将描述以下机制： 氨基葡萄糖可增强3β-HSD1的转录和酶活性。《目标2》将盘问 氨基葡萄糖在3-β-HSD1介导的脱氢表雄酮代谢和CRPC体内发育中的作用目标3将评估 氨基葡萄糖介导的雄激素代谢增加在前列腺癌进展中的临床意义 在调节激素治疗反应中的作用。这一项目的发现有可能为 慢性前列腺癌的综合治疗策略 靶向ADT的代谢紊乱。这项工作将在勒纳研究所进行，地点为 克利夫兰诊所，尼玛·沙里菲博士的实验室。通过这个项目的完成，我将扩大我的知识面 以及前列腺癌生物学和翻译研究方面的技能。关于这些主题的课程作业和研讨会 将补充我的基于研究的培训。作为我职业发展计划的一部分，我还将努力提高 我的科学交流能力，并通过定期演讲获得领导经验，参加 我们学院的科学交流项目，教授本科生生物学课程，并在我们的 博士后协会委员会。我相信，通过完成这一奖学金，我将取得 对前列腺癌研究领域的重大贡献，将成功过渡到 独立的科学家，并将继续对领域和患者护理产生重大影响。

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.