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

项目摘要/摘要 我们的首要目标是确定一种新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前列腺癌的发展和进展 (CRPC)以革命性的长期生存。在美国，前列腺癌的发病率为六分之一， 男性癌症相关死亡的第二大原因。临床上，雄激素剥夺疗法(ADT)与 几十年来，手术或药物去势仍然是晚期/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，CRPC的发展不可避免地伴随着ADT 病人。持续性AR信号轴在CRPC中发挥关键作用的发现导致FDA批准 “第二代”ADT药物，如新型AR拮抗剂苯扎鲁胺/Xtandi，提供4-5个月 生存福利。然而，几乎所有的患者都会在6到12年内对这些新药产生抗药性。 月份。因此，在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。 用于创新的二级/三级化学预防。我们证明了沃堡效应是由 升高的己糖激酶2(HK2)，通过磷酸化催化不可逆的糖酵解第一步 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。相应地，瞄准香港2 酶活性可预防或延缓CRPC。不幸的是，目前的HK2抑制剂，如2-脱氧葡萄糖 (2-DG)，由于抑制普遍表达的HK1而产生的副作用不是特异性的，HK1是 正常细胞的葡萄糖代谢。基于我们公布的数据和初步研究，我们假设 通过靶向依赖eIF4A1的HK2蛋白合成抑制HK2介导的Warburg效应可防止 或延迟CRPC进展。我们将通过实现三个具体目标来检验这一中心假设。目标1是 从结构上阐明CRPC依赖eIF4A1的HK2mRNA翻译的分子机制。 目的2是从遗传学角度证明靶向eIF4A1阻断HK2的mRNA翻译以预防肿瘤 体内生长；目的3是从药理上证明eIF4A1特异性抑制剂西维斯特罗 阻断HK2mRNA的翻译以防止临床前CRPC模型中的肿瘤生长。成功 拟议研究的完成将提供针对eIF4A1-HK2翻译的原则证明 Axis是一种机制驱动的新颖和可行的战略，以防止CRPC在结构、 遗传和药理学水平。

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.