Controlling cancer with aspirin-triggered stimulation of resolution

通过阿司匹林引发的决心刺激来控制癌症

基本信息

批准号：
8547043
负责人：
Dipak Panigrahy
金额：
$ 49.24万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-18 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8547043
关键词：
Adverse effects Animal Model Anti-Inflammatory Agents Anti-inflammatory Aspirin Autacoids Benchmarking Cancer Control Cells Cerebral hemisphere hemorrhage Chemoprevention Chemopreventive Agent Chronic Clinical Clinical Trials Complex Disease Dose Enzymes Epidemiology Event Exhibits Fatty acid glycerol esters Foundations Genetic Genetically Engineered Mouse Goals Growth Hemorrhage Human Human body In Vitro Infiltration Inflammation Inflammation Mediators Inflammatory Injury Intake Leukocytes Lipids Malignant Neoplasms Mediating Mediator of activation protein Modeling Molecular Molecular Mechanisms of Action Mus Neoplasm Metastasis Omega-3 Fatty Acids Pathway interactions Patients Phase Population Pre-Clinical Model Production Prostaglandin-Endoperoxide Synthase Prostaglandins Prostaglandins I Resolution Risk Role Stomach Testing Thromboxane A2 Toxic effect Transgenic Organisms Translations Vent Work anticancer research base cancer prevention cancer risk cancer therapy clinically relevant colon carcinogenesis combat experience gastrointestinal lipid mediator macrophage neoplastic cell novel novel strategies pre-clinical preclinical study prevent promoter receptor research study success tool tumor tumor growth tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): Inflammation in the tumor microenvironment is now recognized as a strong promoter of tumor growth. Substantial epidemiological evidence suggests that aspirin, which suppresses inflammation, also reduces the risk of cancer. However, the mechanism by which aspirin inhibits cancer remains unclear and toxicity has limited its clinical use. Aspirin not only blocks prostaglandin synthesis but, as more recently discovered, also stimulates the production of anti-inflammatory mediators, such as aspirin-triggered resolvins (AT-RvDs). Resolvins are novel pro-resolution lipid mediators derived from omega-3 polyunsaturated fatty acids and are being evaluated as effective anti-inflammatory agents in phase III ocular human clinical trials. We recently discovered that resolvins have potent anti-tumor activity making resolvins important candidates to mediate the anti-cancer activity of aspirin. Thus, we hypothesize that aspirin's tumor-inhibitory effect is mediated in part by aspirin triggered resolvins via novel anti-inflammatory and pro-resolution mechanisms rather than due to blocking prostaglandins alone. The overall goal of this project is to determine whether the anti-cancer activity of resolvins can be harnessed to eradicate cancer by an entirely novel approach which manipulates endogenous pro-resolving mediators. In Aim 1 we will establish in animal models that AT-RvDs have broad anti-cancer activity and elucidate the cellular mechanisms of action that regulate the inflammation-clearing effect of resolvins. This will set the foundation for Aim 2 which is to determine whether aspirin's anti-cancer activity is mediated by AT-RvD1. To abrogate resolvin receptor activity we will use genetically engineered mice that lack the RvD1 receptor ALX/FPR-2 and a pharmacological antagonist of its receptor (ALX/FPR-2). Manipulating the resolvin pathway will also be achieved with transgenic (fat-1) mice which have increased endogenous omega-3 fatty acids (the substrates of AT-RvDs). These studies lay the groundwork to optimize the resolvin pathway to inhibit or prevent cancer in preclinical studies for translation to humans. Thus in Aim 3 we will compare the toxicity profiles of resolvins to aspirin (i.e. in gastric bleeding and aspirin-induced mucosal injury). To determine if resolvins can replace aspirin in chemoprevention experiments, we will recapitulate the human experience with aspirin using the murine model of ApcMin/+ colon carcinogenesis. This pre-clinical characterization will establish a new direction in cancer research and guide us in determining the optimal way to use resolvins in cancer trials in humans. Understanding the role of resolvins in cancer is of direct clinical relevance for two reasons: (1) resolvins may provide a novel pathway and molecular mechanism to explain how aspirin reduces cancer risk so broadly; (2) since resolvins are active at over 10,000-fold lower concentration than aspirin and are naturally produced by the human body, these anti-inflammatory lipid mediators hold great promise to be the safest choice for treatment of chronic inflammatory diseases, including cancer.

描述（由申请人提供）：肿瘤微环境中的炎症现在被认为是肿瘤生长的强大促进剂。大量流行病学证据表明，抑制炎症的阿司匹林还可以降低患癌症的风险。然而，阿司匹林抑制癌症的机制尚不清楚，且毒性限制了其临床应用。阿司匹林不仅会阻碍前列腺素合成，而且最近发现，它还会刺激抗炎介质的产生，例如阿司匹林触发的消退素（AT-RvD）。 Resolvins 是源自 omega-3 多不饱和脂肪酸的新型促分解脂质介质，在 III 期眼部人类临床试验中正在被评估为有效的抗炎剂。我们最近发现解析素具有有效的抗肿瘤活性，这使得解析素成为介导阿司匹林抗癌活性的重要候选者。因此，我们假设阿司匹林的肿瘤抑制作用部分是由阿司匹林介导的通过新型抗炎和促消退机制触发消退素，而不是单独阻断前列腺素。该项目的总体目标是确定是否可以通过操纵内源性促分解介质的全新方法，利用分解素的抗癌活性来根除癌症。在目标 1 中，我们将在动物模型中建立 AT-RvD 具有广泛的抗癌活性，并阐明调节消退素的炎症清除作用的细胞作用机制。这将设置目标 2 的基础是确定阿司匹林的抗癌活性是否由 AT-RvD1 介导。为了消除消退素受体活性，我们将使用缺乏 RvD1 受体 ALX/FPR-2 及其受体药理学拮抗剂 (ALX/FPR-2) 的基因工程小鼠。操纵 resolvin 途径也可以通过转基因 (fat-1) 小鼠来实现，这些小鼠内源性 omega-3 脂肪酸（AT-RvD 的底物）增加。这些研究为优化解析素途径以在临床前研究中抑制或预防癌症并转化为人类奠定了基础。因此，在目标 3 中，我们将比较消解素的毒性特征阿司匹林（即胃出血和阿司匹林引起的粘膜损伤）。确定是否解决可以在化学预防实验中替代阿司匹林，我们将使用 ApcMin/+ 结肠癌发生的小鼠模型来概括人类使用阿司匹林的经验。这一临床前表征将为癌症研究确立新方向，并指导我们确定在人类癌症试验中使用消解素的最佳方法。了解消退素在癌症中的作用具有直接的临床意义，原因有两个：（1）消退素可能提供一种新的途径和分子机制来解释阿司匹林如何广泛降低癌症风险； (2) 由于分解素的活性浓度比阿司匹林低 10,000 多倍，并且是人体自然产生的，因此这些抗炎脂质介质有望成为治疗包括癌症在内的慢性炎症性疾病的最安全选择。