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（由申请人提供）：累积证据表明，腺苷单磷酸激活的蛋白激酶（AMPK）之间存在联系，众所周知的能量稳态和胰岛素敏感性的调节剂，癌细胞的敏感性与通过MTOR信号通路调节的调节，通过炎症性细胞的抑制，尤其是互动的刺激，尤其是i i I互动，蛋白质磷酸酶（PP）2a激活，并调节多种癌基因和肿瘤抑制剂的表达。我们对基于噻唑烷二酮的内部筛查筛选鉴定了铅剂CPD 53，尽管缺乏PPAR激动剂活性，但仍激活AMPK，并抑制LPS诱导的THP-1巨噬细胞中LPS诱导的IL-6分泌，并以低微小的效能，并抑制人体乳腺癌细胞的繁殖，并抑制IC50的繁殖。与AMPK，MTOR-P70S6K信号，AKT和IL-6生产有关的生物标志物。我们假设CPD 53可以在结构上优化，以产生具有亚微米效力的新型AMPK激活剂，可以在临床上可行的浓度和缺乏剂量限制毒性的情况下阻止乳腺肿瘤发生。将执行以下特定目标以检验我们的假设。具体目的1。继续CPD 53的结构修饰并进行最佳剂的机械验证。 CPD 53将通过组合合成进行进一步的修饰，目的是在不同的乳腺癌细胞系中具有低于5M效力的衍生物和癌细胞的选择性，相对于正常的乳腺上皮细胞。最佳候选者将受到与AMPK激活有关的信号传导目标的机械表征。具体目标2。评估MCF-7和MDA-MB-231异种移植肿瘤模型中两个优化AMPK激活剂的体内功效。我们假设用小分子剂靶向AMPK激活构成了抑制乳腺肿瘤生长的潜在成功策略，而与ER和/或其他遗传异常的功能状态无关。与CPD 53和二甲双胍相比，将测试两种结构优化和机械验证的衍生物的体内功效。将确定每种药物的最大耐受剂量，然后评估肿瘤抑制活性，肿瘤内生物标志物调节和毒性。具体目的3。评估最佳AMPK激活剂在致癌物诱导的乳腺肿瘤模型中阻断乳腺肿瘤发生的体内功效。我们假设在AIM 2中鉴定出的最活跃的AMPK激活剂将在临床上可达到的浓度和没有限制性毒性的情况下阻断体内乳腺肿瘤发生。在致癌动物中，还将检查使用该药物的慢性口服治疗的安全性。由于AMPK代表了治疗代谢综合征和癌症的治疗靶标，因此对于这种燃料感应酶的新型药理学激活剂的发展越来越感兴趣。 CPD 53靶向肿瘤代谢的能力以及通过AMPK激活和MTOR信号调节的存活信号传导具有很高的转化价值，可以为乳腺癌开发有效的化学预防策略。