The Origins of Metabolic Reprogramming in Prostate Cancer

前列腺癌代谢重编程的起源

• 批准号: 10310816
• 负责人: Andrew S Goldstein
• 金额: $ 7.67万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-02 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10310816
• 关键词: 3-Dimensional; Androgen Receptor; Androgen Suppression; Androgens; Biological Assay; Cancer Etiology; Carcinoma; Cessation of life; Complement; Development; Disease; Epithelial; Evaluation; Exhibits; Genetic Models; Genetic Transcription; Impairment; Individual; Knowledge; Lipids; Malignant - descriptor; Malignant neoplasm of prostate; Mentorship; Metabolic; Metabolism; Neurosecretory Systems; Organoids; PTEN gene; Parents; Pathway interactions; Patients; Prostate; Prostate Cancer therapy; Proteomics; Pyruvate; Regulation; Research; Resistance; Role; Schools; Signal Transduction; Time; Training; Tumor Suppressor Genes; Tumor Suppressor Proteins; United States; base; castration resistant prostate cancer; cell growth regulation; experimental study; fatty acid oxidation; inhibitor/antagonist; innovation; men; novel strategies; novel therapeutic intervention; oxidation; parent grant; predicting response; preference; prevent; prostate cancer model; protein expression; small molecule inhibitor; stem; targeted treatment; therapeutic target; therapy resistant; transcriptome sequencing; tumor; tumor initiation

PROJECT SUMMARY More than 33,000 individuals in the United States were estimated to die from prostate cancer in 2020, predominantly due to treatment-resistance. As our current therapies are not working for a large number of patients with metastatic castration-resistant prostate cancer, we need innovative strategies to identify new therapeutic approaches. Suppression of the androgen signaling axis with potent androgen receptor pathway inhibitors (ARPIs) has increasingly led to the outgrowth of AR-indifferent tumors that exhibit loss of luminal features and gain of basal and/or neuroendocrine features, termed lineage plasticity or lineage infidelity. Limited knowledge of the factors regulating lineage identity in prostate epithelium has stalled efforts to prevent or reverse lineage plasticity, promote sensitivity to ARPIs, and reduce lethality in CRPC. This proposal stems from our discovery that altering fuel preference is sufficient to modulate lineage identity in prostate epithelium, based on early results from the parent R01. We hypothesize that fuel preference regulates lineage identity and may modulate resistance to ARPIs in CRPC. In Aim 1, we will utilize a 3D organoid assay to modulate fuel preference and define transcriptional and proteomic changes to evaluate lineage identity in normal prostate epithelium. In Aim 2, we will utilize distinct genetic models of prostate cancer driven by tumor suppressor loss (Pten, Rb1) to determine how fuel preference modulates prostate cancer lineage identity. Defining the factors that regulate lineage identity is fundamental to understanding prostate cancer treatment-resistance and may yield therapeutic targets for this lethal disease.

项目总结 据估计，2020年美国有超过3.3万人死于前列腺癌， 主要原因是治疗耐药。因为我们目前的疗法对大量的 患有转移性去势抵抗前列腺癌的患者，我们需要创新的策略来确定新的 治疗方法。通过有效的雄激素受体途径抑制雄激素信号轴 抑制物(ARPI)越来越多地导致AR无关的肿瘤的生长，这些肿瘤表现出管腔的丧失 基本和/或神经内分泌特征的特征和获得，称为谱系可塑性或谱系不忠。有限 对调节前列腺上皮细胞谱系特性的因素的了解阻碍了预防或逆转的努力 谱系可塑性，促进对ARPI的敏感性，并降低CRPC的致死率。这项建议源于我们的 发现改变燃料偏好足以调节前列腺上皮细胞的谱系特性，基于 父代R01的早期结果。我们假设燃料偏好调节血统认同，并可能 调节CRPC对ARPI的抗性。在目标1中，我们将利用3D有机物分析来调节燃料偏好 并定义转录和蛋白质组学变化，以评估正常前列腺上皮的谱系特性。在……里面 目的2，我们将利用肿瘤抑制基因缺失(Pten，Rb1)驱动前列腺癌的不同遗传模型来 确定燃料偏好如何调节前列腺癌谱系认同。定义规范的因素 血统认同是理解前列腺癌治疗耐药的基础，并可能产生治疗效果 这种致命疾病的目标。