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: 10536614
• 负责人: Shivendra Singh
• 金额: $ 42.82万
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10536614
• 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; Epithelium; Experimental Designs; Exposure to; Fatty Acids; Fatty-acid synthase; Formulation; Foundations; Genetic; Genetic Transcription; Glycolysis; Goals; Human; In Vitro; Incidence; Individual; Induction of Apoptosis; Link; 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; Phospholipids; Phytochemical; Placebo Control; Positron-Emission Tomography; Pre-Clinical Model; Prostate; Prostatectomy; Prostatic; Prostatic Intraepithelial Neoplasias; Prostatic Neoplasms; 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; clinical translation; clinically relevant; design; fatty acid metabolism; fatty acid oxidation; human disease; in vivo; in vivo imaging; lipidomics; mRNA Expression; male; men; mortality; mouse model; overexpression; oxidation; pharmacodynamic biomarker; pharmacologic; pilot trial; placebo group; pre-clinical; preclinical study; preventive intervention; primary endpoint; prostate cancer cell; prostate cancer model; prostate cancer prevention; 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.

摘要 科学的预防和假设：使用安全廉价的食用植物化学物质进行化学预防 或药用植物是呼吁减少死亡和患前列腺癌，这继续 是美国男性癌症相关死亡率的主要原因。一种化学预防干预， 前列腺癌仍然缺乏。增加从头合成加上脂肪酸的β-氧化是一个相当 人前列腺癌的独特和靶向机制。上调从头脂肪酸合成的作用 在前列腺癌发病机制中的作用通过显示mRNA/蛋白质水平过表达的研究得到证实 关键脂肪酸合成酶，包括ATP柠檬酸裂解酶（ACLY），乙酰辅酶A羧化酶1（ACC 1）， 和/或脂肪酸合酶（FATIGATION）在早期（前列腺上皮内瘤变; PIN）以及晚期（前列腺上皮内瘤变） （腺癌）疾病时，与正常组织相比。此外，遗传或药物抑制 ACLY、ACC 1和FcB的结合在体外和体内引起前列腺癌细胞生长的抑制。因此，我们认为， 抑制脂肪酸的合成和/或β-氧化代表了化学预防 前列腺癌本实验台-笼-床旁项目的总体目标是确定脂肪酸 使用萝卜硫素（SFN）的前列腺癌的化学预防的代谢抑制，其是主要的 西兰花芽提取物（BSE）中的生物活性植物化学物质。临床前研究旨在测试 SFN和BSE在临床相关转基因中对前列腺癌化学预防作用的假设 小鼠模型（Hi-Myc）与脂肪酸的合成抑制以及β-氧化相关 从而抑制癌细胞增殖。一项试验性双盲、随机化和安慰剂对照研究 还建议在预定行直肠癌切除术的男性中进行机会窗口临床试验，以确定是否 每日口服一种表征良好的BSE制剂（BroccoMax®），其安全性已被证实， 在临床上测试，持续4周导致脂肪酸的循环和前列腺肿瘤水平的抑制。 支持上述假设来自我们自己发表的和初步未发表的研究结果。 具体地说，我们发现SFN处理不仅抑制ACC 1和FXR的蛋白/mRNA水平， 作为与脂肪酸的β-氧化有关的脱氢酶，但也降低人体中的乙酰辅酶A水平。 体外前列腺癌细胞和体内TRAMP小鼠的前列腺肿瘤。乙酰辅酶A是糖尿病的基本组成部分， 在脂肪酸的β-氧化后，线粒体中也会产生脂肪酸。 具体目标：这一高度集中的应用程序的综合具体目标是：（1）确定 SFN介导的抑制脂肪酸合成和β-氧化的潜在机制 前列腺癌和正常前列腺细胞;（2）确定是否通过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;以及（3） 确定连续4周每天口服BroccoMax®是否能减少循环和前列腺肿瘤 通过一项双盲、随机、安慰剂对照的机会窗试验评估脂肪酸水平 男性患者的前列腺切除术 转化影响（显著性）：尽管有丰富的机制数据，但SFN或BSE的临床发展 如用于前列腺癌的化学预防的BroccoMax®取决于：（a）证明 在前列腺癌的临床相关啮齿动物模型中的化学预防功效;（B）鉴定 使用前列腺癌的细胞和临床前啮齿动物模型的药效学生物标志物;和 临床转化研究，以证明从免疫缺陷病毒中鉴定的相同机制生物标志物的调节。 细胞/临床前模型，例如本申请中假设的脂肪酸代谢的抑制。这 研究的逐步进展对于证明更大规模的前列腺癌发病率临床研究是必要的， 主要终点。该项目的前两个具体目标不仅将测试前列腺癌的可能性， SFN和BSE在转基因小鼠模型中的化学预防作用，与人类具有强分子重叠 疾病，但也将鉴定非侵入性药效学生物标志物（例如，血清脂肪酸水平） 适用于特定目标3中的拟定临床试验。