Biomarkers of Sulforaphane/Broccoli Sprout Extract in Prostate Cancer

萝卜硫素/西兰花芽提取物在前列腺癌中的生物标志物

• 批准号: 10314024
• 负责人: Shivendra Singh
• 金额: $ 66.05万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10314024
• 关键词: ATP Citrate (pro-S)-Lyase; Acetates; Acetyl Coenzyme A; Acetyl-CoA Carboxylase; Adenocarcinoma; Affect; American; Biochemical; Bioenergetics; Biological Availability; Biological Markers; Broccoli - dietary; Cancer Cell Growth; Cancer Etiology; Cell Proliferation; Cell model; Cells; Cessation of life; Chemoprevention; Chemopreventive Agent; Clinical; Clinical Research; Clinical Trials; Coupled; Data; Dietary Administration; Disease; Double-Blind Method; Down-Regulation; Edible Plants; Enzyme Inhibition; Enzymes; Epithelial; Exposure to; Fatty Acids; Fatty-acid synthase; Formulation; Foundations; Genetic; Genetic Transcription; Glycolysis; Goals; Human; In Vitro; Incidence; Individual; Induction of Apoptosis; Intervention; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Malonyl Coenzyme A; Mediating; Medicinal Plants; Messenger RNA; Mitochondria; Molecular; Morbidity - disease rate; Mus; Neoplasms; Nonesterified Fatty Acids; Normal tissue morphology; Oral; Oral Administration; Outcome Study; Oxidoreductase; PTEN gene; Pathogenesis; Pathway interactions; Pharmacology; Phospholipids; Phytochemical; Placebo Control; Positron-Emission Tomography; Pre-Clinical Model; Prostate; Prostatectomy; Prostatic; Prostatic Intraepithelial Neoplasias; Prostatic Neoplasms; Protein Inhibition; Proteins; Publishing; Randomized; Research; Rodent Model; Role; SRE-1 binding protein; Safety; Schedule; Serum; Solid Neoplasm; Sulforaphane; Technology; Testing; Transgenic Mice; Warburg Effect; c-myc Genes; cancer cell; cancer chemoprevention; clinical development; clinically relevant; design; experimental study; fatty acid metabolism; fatty acid oxidation; human disease; in vivo; in vivo imaging; lipidomics; male; men; mortality; mouse model; overexpression; oxidation; pharmacodynamic biomarker; pilot trial; placebo group; pre-clinical; preclinical study; primary endpoint; prostate cancer cell; prostate cancer model; secondary endpoint; transgenic adenocarcinoma of mouse prostate; translational impact; translational study; tumor; uptake

ABSTRACT Scientific Premise and Hypothesis: Chemoprevention using safe and inexpensive phytochemicals from edible or medicinal plants is appealing for reducing the death and suffering from prostate cancer, which continues to be a leading cause of cancer-linked mortality among American men. A chemopreventative intervention for prostate cancer is still lacking. Increased de novo synthesis coupled with β-oxidation of fatty acids is a rather unique and targetable mechanism of human prostate cancer. A role for upregulated de novo fatty acid synthesis in pathogenesis of prostate cancer is substantiated by studies showing overexpression of mRNA/protein levels of key fatty acid synthesis enzymes, including ATP citrate lyase (ACLY), acetyl-CoA carboxylase 1 (ACC1), and/or fatty acid synthase (FASN) in early (prostatic intraepitheilial neoplasia; PIN) as well as advanced (adenocarcinoma) disease when compared to normal tissue. In addition, genetic or pharmacological suppression of ACLY, ACC1, and FASN causes inhibition of prostate cancer cell growth in vitro and in vivo. Therefore, inhibition of synthesis and/or β-oxidation of fatty acids represents a promising strategy for chemoprevention of prostate cancer. The overall goal of this bench-cage-bedside project is to determine the feasibility of fatty acid metabolism inhibition for chemoprevention of prostate cancer using sulforaphane (SFN), which is the principal bioactive phytochemical in broccoli sprout extract (BSE). The preclinical studies are conceived to test the hypothesis that prostate cancer chemoprevention by SFN and BSE in a clinically-relevant transgenic mouse model (Hi-Myc) is associated with suppression of synthesis as well as β-oxidation of fatty acids leading to inhibition of cancer cell proliferation. A pilot double-blind, randomized, and placebo-controlled window of opportunity clinical trial in men scheduled for prostatectomy is also proposed to determine whether daily oral administration of a well-characterized BSE formulation (BroccoMax®), the safety of which has already been tested clinically, for 4 weeks leads to suppression of circulating and prostate tumor levels of fatty acids. Support for the above stated hypothesis derives from our own published and preliminary unpublished findings. Specifically, we found that SFN treatment not only suppresses protein/mRNA levels of ACC1 and FASN as well as the dehydrogenases implicated in β-oxidation of fatty acids but also decreases acetyl-CoA levels in human prostate cancer cells in vitro and prostate tumors of TRAMP mice in vivo. Acetyl-CoA is the building block of de novo fatty acid synthesis but is also generated in the mitochondria upon β-oxidation of fatty acids. Specific Aims: The well-integrated specific aims of this highly-focused application are to: (1) Determine the mechanism underlying SFN-mediated inhibition of fatty acid synthesis and β-oxidation using cellular models of prostate cancer and normal prostate cells; (2) Determine whether prostate cancer chemoprevention by SFN and BSE in Hi-Myc transgenic mice is associated with inhibition of fatty acid synthesis and β-oxidation; and (3) Determine whether daily oral BroccoMax® administration for 4 weeks decreases circulating and prostate tumor levels of fatty acids through a pilot double-blind, randomized, and placebo-controlled window of opportunity trial in men scheduled for prostatectomy. Translational Impact (Significance): Despite wealth of mechanistic data, clinical development of SFN or BSE like BroccoMax® for chemoprevention of prostate cancer is contingent upon: (a) demonstration of chemopreventive efficacy in a clinically-relevant rodent model of prostate cancer; (b) identification of pharmacodynamic biomarker(s) using cellular and preclinical rodent models of prostate cancer; and (c) pilot clinical translational studies to demonstrate modulation of the same mechanistic biomarker(s) identified from the cellular/preclinical models such as suppression of fatty acid metabolism hypothesized in this application. This stepwise progression of research is essential to justify a larger clinical study with prostate cancer incidence as the primary end point. The first two specific aims of this project will not only test the possibility of prostate cancer chemoprevention by SFN and BSE in a transgenic mouse model with strong molecular overlap with the human disease but will also identify non-invasive pharmacodynamic biomarker(s) (e.g., serum levels of fatty acids) applicable to the proposed clinical trial in specific aim 3.

抽象的 科学前提和假设：使用可食用的安全且廉价的理化学物质进行化学预防 或者正在出现药用植物，以减少死亡和患有前列腺癌的痛苦，这继续 成为美国男性癌症与癌症死亡率的主要原因。化学预防干预措施 前列腺癌仍然缺乏。从头合成增加，脂肪酸的β氧化是一种相当的 人类前列腺癌的独特和目标机制。从头脂肪酸合成的上调的作用 在前列腺癌的发病机理中，通过显示mRNA/蛋白质水平过表达的研究证实了 钥匙脂肪酸合成酶，包括ATP柠檬酸裂解酸酯（ACLY），乙酰-COA羧化酶1（ACC1）， 和/或脂肪酸合酶（FASN）早期（前列腺上皮内肿瘤； PIN）以及晚期 与正常组织相比（腺癌）疾病。另外，遗传或药理抑制 Acly，ACC1和FASN的体外和体内会导致前列腺癌细胞生长的抑制。所以， 抑制脂肪酸的合成和/或β-氧化代表了化学预防的希望策略 前列腺癌。这个台式式床边项目的总体目标是确定脂肪酸的可行性 使用Sulforaphane（SFN）对前列腺癌进行化学预防的代谢抑制，这是主要的 西兰花发芽提取物（BSE）中的生物活性植物化学。临床前研究被认为是为了测试 假设SFN和BSE在与临床相关的转基因中进行了前列腺癌化学预防 小鼠模型（HI-MYC）与抑制脂肪酸的抑制以及β-氧化有关 导致抑制癌细胞增殖。飞行员双盲，随机和安慰剂对照 还提出了计划进行前列腺切除术的男性的机会临床试验窗口临床试验以确定是否是否 每日口服特征良好的BSE公式（Broccomax®），其安全性已经 我们在临床上进行了4周的测试，导致抑制循环和前列腺肿瘤水平的脂肪酸水平。 对上述假设的支持来自我们自己发表的初步未发表的发现。 具体而言，我们发现SFN处理不仅抑制了ACC1和FASN的蛋白质/mRNA水平 由于脱氢酶在脂肪酸的β-氧化中实施，但也下降了人类的乙酰-COA水平 在体内流浪小鼠的体外和前列腺肿瘤的前列腺癌细胞。乙酰辅酶A是DE的基础 Novo脂肪酸合成，但在脂肪酸的β-氧化后也会在线粒体中产生。 具体目的：此高度关注的应用的整合良好的具体目的是：（1）确定 SFN介导的抑制脂肪酸合成和β-氧化的机制使用细胞模型 前列腺癌和正常的前列腺细胞； （2）确定前列腺癌是否对SFN和SFN和 Hi-Myc转基因小鼠中的BSE与脂肪酸合成和β-氧化的抑制有关。 （3） 确定每日口服broccomax®在4周内的给药是否会下降循环和前列腺肿瘤 通过飞行员双盲，随机和安慰剂控制的机会试验窗口的脂肪酸水平 在计划进行前列腺切除术的男性中。 翻译影响（意义）：尽管机械数据丰富，SFN或BSE的临床发展 像Broccomax®用于化学预防的前列腺癌的化学预防一样，也取决于：（a）证明 在前列腺癌的临床啮齿动物模型中的化学预防效率； （b）识别 使用前列腺癌的细胞和临床前啮齿动物模型，药物动态生物标志物； （c）飞行员 临床翻译研究证明了对从相同机械生物标志物的调节 在本应用中假设的脂肪酸代谢抑制等细胞/临床前模型。这 研究的逐步进展对于证明具有前列腺癌发病率的更大临床研究至关重要 主要终点。该项目的前两个具体目标不仅会测试前列腺癌的可能性 SFN和BSE的化学预防在具有强分子重叠的转基因小鼠模型中 疾病，但还将鉴定出非侵入性药效生物标志物（S）（例如，脂肪酸的血清水平） 适用于特定目标3的拟议临床试验。