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Novel AMPK Activators in Breast Cancer Prevention

预防乳腺癌的新型 AMPK 激活剂

基本信息

批准号：
8327114
负责人：
CHING-SHIH CHEN
金额：
$ 19.9万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8327114
关键词：
2,4-thiazolidinedione 70-kDa Ribosomal Protein S6 Kinases Adenosine Monophosphate Adverse effects Agonist Animals Autophagocytosis Biological Markers Breast Breast Cancer Cell Breast Cancer Model Breast Cancer Prevention Cancer Cell Growth Cancer Etiology Cancer Hospital Cancer cell line Carcinogens Cell Survival Cessation of life Chemopreventive Agent Chronic Clinical Management Combinatorial Synthesis Data Defect Development Disease Dose-Limiting Drug Delivery Systems Effectiveness Enzymes Epidemiology Epigenetic Process Epithelial Cells Evaluation Exhibits Family Genetic Goals Growth Factor Heterogeneity Histone Deacetylase Inhibitor Homeostasis Homologous Gene Housing Human Incidence Indole-3-Carbinol Induction of Apoptosis Inflammatory Inhibitory Concentration 50 Interleukin-6 Laboratories Lead Libraries Light Link Longevity Lung MCF7 cell Malignant Neoplasms Mammary Neoplasms Mammary Tumorigenesis Maximum Tolerated Dose Metabolic syndrome Metabolism Metformin Modeling Modification Molecular Molecular Abnormality Molecular Target Oral Other Genetics Parents Pathway interactions Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Phase I Clinical Trials Prevention strategy Production Prostate Protein Dephosphorylation Protein Kinase Protein phosphatase Regulation Research Resources Ribose Safety Screening procedure Second Primary Cancers Signal Pathway Signal Transduction Sirolimus Testing Thiazolidinediones Toxic effect Transgenic Mice Tumor Suppressor Genes Validation Woman analog base cancer cell cancer diagnosis cancer prevention cancer risk cancer therapy carcinogenesis ciglitazone clinically relevant cytokine design diabetic patient drug discovery functional status gastrointestinal in vivo inhibitor/antagonist insulin sensitivity interest macrophage malignant breast neoplasm mouse model novel pre-clinical prevent response small molecule tumor tumor growth tumor xenograft tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Accumulating evidence suggests a link between adenosine monophosphate-activated protein kinase (AMPK), a well known regulator of energy homeostasis and insulin sensitivity, and cancer cell growth and survival through the regulation of mTOR signaling pathways, the suppression of inflammatory cytokines, especially interleukin (IL)-6, the stimulation of Akt dephosphorylation through protein phosphatase (PP)2A activation, and modulation of the expression of multiple oncogenes and tumor suppressors. Our screening of an in-house, thiazolidinedione-based focused compound library identified a lead agent, Cpd 53, that despite lacking PPAR agonist activity, activates AMPK and inhibits LPS-induced IL-6 secretion in THP-1 macrophages with low microM potency, and inhibits the proliferation of human breast cancer cells with IC50 of 1 - 2 microM by modulating the functional/expression status of various biomarkers related to AMPK, mTOR-p70S6K signaling, Akt, and IL-6 production. We hypothesize that Cpd 53 can be structurally optimized to generate novel AMPK activators with sub-microM potency that can block mammary tumorigenesis at clinically feasible concentrations and in the absence of dose-limiting toxicities. The following Specific Aims will be carried out to test our hypothesis. Specific Aim 1. To continue the structural modification of Cpd 53 and to conduct mechanistic validation of optimal agents. Cpd 53 will undergo further modifications via combinatorial synthesis with the goal of generating derivatives with sub-5M potency and cancer cell selectivity in different breast cancer cell lines vis-`- vis normal breast epithelial cells. The optimal candidate(s) will be subjected to mechanistic characterizations of signaling targets pertinent to AMPK activation. Specific Aim 2. To assess the in vivo efficacy of two optimized AMPK activators in MCF-7 and MDA-MB-231 xenograft tumor models. We hypothesize that targeting AMPK activation with a small-molecule agent constitutes a potentially successful strategy to suppress breast tumor growth irrespective of the functional status of ER and/or other genetic abnormalities. Two structurally optimized and mechanistically validated derivatives will be tested for in vivo efficacy in comparison to Cpd 53 and metformin. Maximum tolerated doses for each agent will be determined, followed by evaluation of tumor suppressive activity, intratumoral biomarker modulation, and toxicity. Specific Aim 3. To assess the in vivo efficacy of the optimal AMPK activator to block mammary tumorigenesis in a carcinogen-induced mammary tumor model. We hypothesize that the most active AMPK activator identified in Aim 2 will block mammary tumorigenesis in vivo at clinically attainable concentrations and in the absence of limiting toxicity. The safety of chronic oral treatment with this agent will also be examined in carcinogen-untreated animals. As AMPK represents a therapeutically relevant target for the treatment of the metabolic syndrome and cancer, there is a growing interest in the development of novel pharmacological activators for this fuel-sensing enzyme. Cpd 53's ability to target tumor metabolism, and survival signaling via AMPK activation and modulation of mTOR signaling is of high translational value to develop an effective chemopreventive strategy for breast cancer.

描述(申请人提供)：越来越多的证据表明，众所周知的能量平衡和胰岛素敏感性调节因子一磷酸腺苷激活的蛋白激酶(AMPK)与癌细胞的生长和生存有关，它通过调节mTOR信号通路，抑制炎症细胞因子，特别是白细胞介素6(IL-6)，通过蛋白磷酸酶(PP)2A激活刺激Akt去磷酸化，以及调节多种癌基因和肿瘤抑制因子的表达，与癌细胞的生长和存活有关。我们对基于噻唑烷二酮的内部重点化合物文库的筛选发现了一种先导剂CPD 53，尽管缺乏PPAR激动剂活性，但它可以激活AMPK并抑制低微米THP-1巨噬细胞中内毒素诱导的IL-6的分泌，并通过调节与AMPK、mTOR-p70S6K信号、Akt和IL-6产生相关的各种生物标记物的功能/表达状态来抑制IC50为1-2微米的人乳腺癌细胞的增殖。我们假设CPD 53可以被结构优化以产生具有亚微米效力的新型AMPK激活剂，该激活剂可以在临床可行的浓度下阻止乳腺肿瘤的发生，并且没有剂量限制的毒性。为了验证我们的假设，我们将实现以下具体目标。具体目标1.继续CPD 53的结构修饰，并对最佳试剂进行机械验证。CPD 53将通过组合合成进行进一步的修饰，目标是在不同的乳腺癌细胞系中产生相对于正常乳腺上皮细胞具有低于5M效力和癌细胞选择性的衍生物。最佳候选者(S)将接受与AMPK激活相关的信号靶标的机械性表征。具体目的2.评价两种优化的AMPK激活剂对MCF-7和MDA-MB-231移植瘤模型的体内疗效。我们假设，无论ER的功能状态和/或其他遗传异常如何，用小分子药物靶向AMPK激活构成了一个潜在的成功的策略来抑制乳腺癌的生长。两种结构优化和机械验证的衍生物将进行体内疗效测试，并与CPD 53和二甲双胍进行比较。将确定每种药物的最大耐受量，然后评估肿瘤抑制活性、肿瘤内生物标记物调节和毒性。具体目的3.评价最佳AMPK激活剂在致癌物诱导的乳腺肿瘤模型中阻断乳腺肿瘤形成的体内效果。我们推测，在AIM 2中发现的最活跃的AMPK激活剂将在临床可获得的浓度下在体内阻止乳腺肿瘤的发生，并且没有限制性毒性。用这种药物进行慢性口服治疗的安全性也将在没有接受致癌物治疗的动物身上进行检验。由于AMPK代表了治疗代谢综合征和癌症的相关靶点，人们对开发这种燃料敏感酶的新型药理激活剂的兴趣越来越大。CPD 53‘S通过激活AMPK和调节mTOR信号来靶向肿瘤代谢和生存信号的能力，对于开发有效的乳腺癌化学预防策略具有很高的翻译价值。