Colon Cancer Chemoprevention with Phosphodiesterase-5 Inhibitors

使用磷酸二酯酶 5 抑制剂进行结肠癌化学预防

• 批准号: 8579446
• 负责人: Darren D. Browning
• 金额: $ 30.92万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8579446
• 关键词: Adhesions; Animals; Azoxymethane; Cancer Model; Cell Line; Chemoprevention; Colitis; Colon; Colon Carcinoma; Colorectal Cancer; Cyclic GMP; Cytokine Gene; Data; Development; Disease; Dose; Drug usage; Endotoxins; Epithelial; Epithelial Cells; Epithelium; Exhibits; Gastrointestinal Diseases; Gene Expression; Genes; Goals; Human; Inflammation; Injection of therapeutic agent; Intestines; Laboratories; Luciferases; Maintenance; Measures; Molecular Target; Mucin-2 Staining Method; Mucositis; Mucous Membrane; Mus; Oral; Outcome; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Pre-Clinical Model; Predisposition; Prevention approach; Process; Proteins; Regulation; Reporter; Research; Role; Severity of illness; Signal Pathway; Signal Transduction; Small Interfering RNA; Sodium Dextran Sulfate; Staging; Testing; Therapeutic; Tissues; Tumor Suppression; Tumor Suppressor Proteins; Ulcerative Colitis; Wild Type Mouse; Work; base; cancer chemoprevention; cancer prevention; cancer therapy; claudin 4; clinically relevant; high risk; human PRKG2 protein; inhibitor/antagonist; mortality; novel; novel therapeutic intervention; phosphodiesterase V; prevent; promoter; public health relevance; research study; sildenafil; tadalafil; tumor; tumor initiation; tumor progression; tumorigenesis; vardenafil

DESCRIPTION (provided by applicant): Colorectal cancer has a high mortality because it is typically detected at a late stage when treatment options are limited. Chemoprevention is therefore an important therapeutic strategy, and for high-risk patients the development of new drugs is a high priority. The epithelial layer suppresses inflammation in the colon by separating luminal contents from underlying tissues. Increasing epithelial barrier function is an important approach to prevention because inflammation is central to both tumor initiation and progression. Several lines of evidence from independent laboratories indicate that cGMP signaling is tumor suppressive in the intestine and might be harnessed as part of a novel treatment paradigm. Our long-term goal is to prevent and treat colon cancer and associated gastrointestinal disease by exploiting cGMP-signaling in the colon epithelium. Our central hypothesis is that signaling through PKG2 is barrier protective, and that this pathway can be harnessed for colon cancer prevention. Our objectives are: (1) to gain detailed information about cGMP/PKG2 signaling in the colon epithelium, (2) to test the importance of PKG2 in barrier-protection and tumor suppression, (3) to determine whether activation of PKG2 signaling by PDE-5 inhibitors is chemopreventative in preclinical models of colon cancer. We will test our central hypothesis and thereby accomplish the objective of this project by completion of the following aims: Aim 1: Test the hypothesis that DUSP10 and Claudin-4 are key effectors of cGMP/PKG2 signaling in colon epithelial cells. Aim 2: Test the hypothesis that PKG2 is barrier-protective in the colon epithelium. Aim 3: Test the hypothesis that PKG2 is tumor-suppressive in the colon and that activation with clinically relevant PDE-5 inhibitors is an effective chemoprevention strategy. The experiments proposed will measure the effect of PKG2 signaling and it's activation by PDE-5 inhibitors on barrier function, inflammation, and tumorigenesis using Prkg2-/- mice and both DSS/AOM and ApcMin/+ mouse cancer models. Our expected outcomes include detailed information about: (1) PKG2-dependent signaling in the colon epithelium and how it controls barrier integrity and susceptibility to colitis and colon cancer, and (2) the utility of PKG2 activation using clinically relevant PDE-5 inhibitors as a colon cancer chemoprevention strategy. Our projects impact will be the identification of a novel barrier-protective signaling pathway in the colon epithelium, and demonstration that this pathway can be targeted for colon cancer chemoprevention using drugs already proven safe in humans.

描述（由申请人提供）：结直肠癌死亡率很高，因为它通常在治疗选择有限的晚期才被发现。因此，化学预防是一种重要的治疗策略，对于高危患者来说，新药的开发是重中之重。上皮层通过将管腔内容物与下面的组织分离来抑制结肠炎症。增加上皮屏障功能是一种重要的预防方法，因为炎症是肿瘤发生和进展的核心。来自独立实验室的多条证据表明，cGMP 信号传导在肠道中具有肿瘤抑制作用，并且可能被用作新型治疗范例的一部分。我们的长期目标是通过利用结肠上皮细胞中的 cGMP 信号来预防和治疗结肠癌及相关胃肠道疾病。我们的中心假设是，通过 PKG2 的信号传导具有屏障保护作用，并且该通路可用于预防结肠癌。我们的目标是：(1) 获得有关结肠上皮中 cGMP/PKG2 信号传导的详细信息，(2) 测试 PKG2 在屏障保护和肿瘤抑制中的重要性，(3) 确定 PDE-5 抑制剂激活 PKG2 信号传导是否在结肠癌临床前模型中具有化学预防作用。我们将测试我们的中心假设，从而通过完成以下目标来实现该项目的目标： 目标 1：测试 DUSP10 和 Claudin-4 是结肠上皮细胞中 cGMP/PKG2 信号转导的关键效应子的假设。目标 2：检验 PKG2 在结肠上皮中具有屏障保护作用的假设。目标 3：检验以下假设：PKG2 在结肠中具有肿瘤抑制作用，并且用临床相关的 PDE-5 抑制剂激活是一种有效的化学预防策略。拟议的实验将使用 Prkg2-/- 小鼠以及 DSS/AOM 和 ApcMin/+ 小鼠癌症模型来测量 PKG2 信号传导及其由 PDE-5 抑制剂激活对屏障功能、炎症和肿瘤发生的影响。我们的预期结果包括以下详细信息：(1) 结肠上皮中的 PKG2 依赖性信号传导及其如何控制屏障完整性和对结肠炎和结肠癌的易感性，以及 (2) 使用临床相关的 PDE-5 抑制剂激活 PKG2 作为结肠癌化学预防策略的效用。我们的项目影响将是鉴定结肠上皮中的一种新型屏障保护信号通路，并证明该通路可以使用已被证明对人类安全的药物进行结肠癌化学预防。