Targeting eIF4A1-dependent HK2 translation axis for prevention of castration-resistant prostate cancer

靶向 eIF4A1 依赖性 HK2 翻译轴预防去势抵抗性前列腺癌

基本信息

批准号：
10051412
负责人：
YIBIN DENG
金额：
$ 39.46万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10051412
关键词：
5&apos Untranslated Regions AKT1 gene Ablation Androgen Receptor Androgens Binding Sites Biological CRISPR/Cas technology Cancer Etiology Cancer Patient Cancer cell line Castration Cessation of life Chemoprevention Clinical Complex Crystallization Data Deoxyglucose Development Doxycycline G-Quartets Generations Genes Genetic Genetic Models for Cancer Genetic Transcription Genetic Translation Genetic study Glucose Glucose-6-Phosphate Glycolysis Goals Hexokinase 2 Human Introns Knock-out Lentivirus Malignant neoplasm of prostate Mediating Medical Castration Messenger RNA Metastatic Prostate Cancer Molecular Mus Mutagenesis Mutation Normal Cell Occupations PTEN gene Patients Pharmaceutical Preparations Pharmacology Play Prevention Protein Biosynthesis Proteins Proto-Oncogene Proteins c-akt Publishing RNA Receptor Signaling Resistance development Role Secondary Prevention Structure System TP53 gene Testing Tissues Toxic effect Translations Tumor Suppressor Genes United States Warburg Effect androgen deprivation therapy base castration resistant prostate cancer clinical application drug development druggable target glucose metabolism in vivo inhibitor/antagonist innovation mRNA Transcript Degradation men novel novel therapeutics patient derived xenograft model pre-clinical preclinical development prevent prostate cancer cell prostate cancer cell line prostate cancer model prostate cancer progression protein expression public health relevance side effect silvestrol small hairpin RNA standard of care translational impact tumor growth

项目摘要

Project Summary/Abstract Our overarching goal is to identify a novel mechanism-driven chemoprevention strategy that can effectively prevent or delay the development and progression of currently incurable castration-resistant prostate cancer (CRPC) to revolutionize long-term survival. In the United States, prostate cancer strikes one in six men and is the second leading cause of cancer-related deaths in men. Clinically, androgen deprivation therapy (ADT) with surgical or medical castration remains standard-of-care for advanced/metastatic prostate cancer for decades. Despite its efficacy in the short term, ADT is inevitably followed by the development of CRPC in the majority of patients. The discovery that persistent AR signaling axis plays a crucial role in CRPC led to FDA-approval of “second-generation” ADT drugs, such as the novel AR antagonist enzalutamide/Xtandi, providing 4-5 months survival benefits. However, nearly all the patients will develop resistance to these new drugs within 6 to 12 months. Thus, development of CRPC following ADT is a major clinical problem but presents a unique window for innovative secondary/tertiary chemoprevention. We demonstrate that Warburg effect caused by the elevated hexokinase 2 (HK2), which catalyzes the irreversible first step of glycolysis by phosphorylating glucose to glucose-6-phosphate (G-6-P), is required for tumor growth of CRPC. Accordingly, targeting HK2 enzymatic activity could prevent or delay CRPC. Unfortunately, current HK2 inhibitors, such as 2-deoxyglucose (2-DG), are not specific with side effects due to inhibition of ubiquitously expressed HK1, which is required for glucose metabolism of normal cells. Based on our published data and preliminary studies, we hypothesize that inhibition of HK2-mediated Warburg effect by targeting eIF4A1-dependent HK2 protein synthesis prevents or delays CRPC progression. We will test this central hypothesis by accomplishing 3 specific aims. Aim 1 is to structurally elucidate the molecular mechanism underlying eIF4A1-dependent HK2 mRNA translation in CRPC. Aim 2 is to genetically demonstrate that targeting eIF4A1 blocks HK2 mRNA translation to prevent tumor growth of CRPC in vivo; and Aim 3 is to pharmacologically demonstrate that eIF4A1specific inhibitor silvestrol blocks HK2 mRNA translation to prevent tumor growth in preclinical CRPC models. Successful accomplishment of the proposed studies will provide Proof-of-Principle that targeting eIF4A1-HK2 translation axis serves as a mechanisms-driven novel and actionable strategy to prevent CRPC progression at structural, genetic and pharmacological levels.

项目概要/摘要我们的首要目标是确定一种新颖的机制驱动的化学预防策略，该策略可以有效地预防或延缓目前无法治愈的去势抵抗性前列腺癌的发生和进展 (CRPC) 彻底改变了长期生存在美国，六分之一的男性患有前列腺癌，并且正在发生。临床上，雄激素剥夺疗法（ADT）是男性癌症相关死亡的第二大原因。几十年来，手术或药物阉割仍然是晚期/转移性前列腺癌的标准治疗方法。尽管ADT在短期内有效，但在大多数情况下，ADT不可避免地会发展为CRPC。持续性 AR 信号轴在 CRPC 中发挥关键作用的发现导致 FDA 批准了该药物。 “第二代”ADT 药物，例如新型 AR 拮抗剂 enzalutamide/Xtandi，可提供 4-5 个月的疗效然而，几乎所有患者都会在 6 至 12 年内对这些新药产生耐药性。因此，ADT 后发生 CRPC 是一个主要的临床问题，但提供了一个独特的窗口。我们证明了由 Warburg 效应引起的创新二级/三级化学预防。己糖激酶 2 (HK2) 升高，通过磷酸化催化糖酵解的不可逆第一步葡萄糖转化为葡萄糖-6-磷酸 (G-6-P) 是 CRPC 肿瘤生长所必需的，因此，靶向 HK2。不幸的是，目前的 HK2 抑制剂，例如 2-脱氧葡萄糖，可以预防或延迟 CRPC。 (2-DG)，由于抑制普遍表达的 HK1，因此不具有特异性副作用，而 HK1 是根据我们发表的数据和初步研究，我们发现正常细胞的葡萄糖代谢。通过靶向 eIF4A1 依赖性 HK2 蛋白合成来抑制 HK2 介导的 Warburg 效应可防止我们将通过实现 3 个具体目标来检验这一中心假设。从结构上阐明 CRPC 中 eIF4A1 依赖性 HK2 mRNA 翻译的分子机制。目标 2 是从遗传学角度证明靶向 eIF4A1 可以阻断 HK2 mRNA 翻译以预防肿瘤 CRPC在体内的生长；目标3是从药理学角度证明eIF4A1特异性抑制剂silvestrol 阻断 HK2 mRNA 翻译以防止临床前 CRPC 模型中的肿瘤生长。拟议研究的完成将为靶向 eIF4A1-HK2 翻译提供原理验证轴作为一种机制驱动的新颖且可行的策略来防止 CRPC 在结构、遗传和药理学水平。