Novel Energy Restriction-Mimetic Agents for Prostate Cancer Prevention

描述（由申请人提供）：癌细胞通过将细胞代谢转变为有氧糖酵解，即所谓的瓦尔堡效应，在微环境中获得生长优势。人们越来越关注通过利用恶性细胞与正常细胞对糖酵解抑制的敏感性差异来靶向有氧糖酵解用于癌症治疗，其中概念验证由饮食热量限制和基于天然产物的能量限制模拟剂（ERMA）提供，例如白藜芦醇和2-脱氧葡萄糖（2-DG）在实验动物模型中抑制致癌作用。然而，白藜芦醇和2-DG的临床应用受到其弱效力的阻碍。我们的研究已经确定噻唑烷二酮类（TZDs）作为一类新的ERMAs，因为它们引起了标志性的细胞反应特征的能量限制，包括瞬时诱导沉默信息调节因子（Sirt）1的表达，激活细胞内燃料传感器AMP激活的蛋白激酶（AMPK），和内质网（ER）的压力，其中的相互作用最终导致自噬和凋亡性细胞死亡。这些结果为TZDs的先导物优化提供了分子基础，TZDs的先导物OSU-CG 12（CG 12）通过阻断葡萄糖摄取而抑制肿瘤代谢的能力比白藜芦醇高一个数量级。因此，这一竞争性更新提案旨在测试CG 12靶向能量代谢的独特能力在前列腺癌预防中具有转化潜力的假设。提出了三个具体目标。目的1是进行CG 12在介导能量限制中的作用模式的机制表征。我们将确定CG 12对葡萄糖利用的抑制作用的机制，研究p53在CG 12诱导的细胞凋亡和自噬性细胞死亡中的作用，并研究CG 12介导的HIF-1a抑制的机制，HIF-1a通过糖酵解的代谢转换和2-DG抗性的发展在调节细胞代谢中起着关键作用。目标2是继续对CG 12进行先导优化，以开发有效的ERMA。目的3是评估优化的ERMA在TRAMP和PTEN缺陷小鼠模型中阻断前列腺肿瘤发生的体内功效。总之，拟议的研究将有效地将我们的新发现，即TZDs独特地靶向肿瘤代谢，转化为一类具有显著化学预防潜力的新型ERMA的临床前开发。

DESCRIPTION (provided by applicant): Cancer cells gain growth advantages in the microenvironment by shifting cellular metabolism to aerobic glycolysis, the so-called Warburg effect. There is a growing interest in targeting aerobic glycolysis for cancer therapy by exploiting the differential susceptibility of malignant versus normal cells to glycolytic inhibition, of which the proof-of-concept is provided by the in vivo efficacy of dietary caloric restriction and natural product-based energy restriction-mimetic agents (ERMAs) such as resveratrol and 2-deoxyglucose (2-DG) in suppressing carcinogenesis in experimental animal models. The clinical applications of resveratrol and 2-DG, however, are hampered by their weak potencies. Our studies have identified thiazolidinediones (TZDs) as a novel class of ERMAs in that they elicited hallmark cellular responses characteristic of energy restriction, including transient induction of silent information regulator (Sirt)1 expression, activation of the intracellular fuel sensor AMP-activated protein kinase (AMPK), and endoplasmic reticulum (ER) stress, the interplay among which culminated in autophagic and apoptotic cell death. These results provided a molecular basis to conduct lead optimization of TZDs, which netted OSU-CG12 (CG12) exhibiting an-order-of-magnitude higher potency than resveratrol in restricting tumor metabolism by blocking glucose uptake. Thus, this competing renewal proposal is aimed at testing the hypothesis that the unique ability of CG12 to target energy metabolism has translational potential in prostate cancer prevention. Three Specific Aims are proposed. Aim 1 is to conduct the mechanistic characterization of the mode of action of CG12 in mediating energy restriction. We will identify the mechanism underlying the suppressive effects of CG12 on glucose utilization, examine the role of p53 in CG12-induced apoptotic and autophagic cell death, and investigate the mechanism underlying CG12-mediated suppression of HIF-1a, which plays a critical role in regulating cell metabolism through the metabolic switch to glycolysis and the development of resistance to 2-DG. Aim 2 is to continue the lead optimization of CG12 to develop potent ERMAs. Aim 3 is to assess the in vivo efficacy of an optimized ERMA to block prostate tumorigenesis in the TRAMP and PTEN-deficient mouse models. Together, the proposed studies will effectively translate our novel finding that TZDs uniquely target tumor metabolism to preclinical development of a novel class of ERMAs with significant chemopreventive potential.