Colon Cancer Chemoprevention with Phosphodiesterase-5 Inhibitors

描述（由申请人提供）：结直肠癌的死亡率很高，因为它通常在治疗选择有限的晚期才被发现。因此，化学预防是一项重要的治疗策略，对于高危患者，开发新药是当务之急。上皮层通过将管腔内容物与下层组织分离来抑制结肠炎症。增加上皮屏障功能是预防肿瘤的重要途径，因为炎症是肿瘤发生和发展的核心。来自独立实验室的几条证据表明，cGMP信号在肠道中具有肿瘤抑制作用，可能作为一种新的治疗模式的一部分加以利用。我们的长期目标是通过利用结肠上皮中的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信号传导具有屏障保护作用，并且该途径可以用于结肠癌的预防。我们的目标是：(1)获得结肠上皮中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。我们将通过完成以下目标来验证我们的中心假设，从而实现本项目的目标：目的1：验证DUSP10和Claudin-4是结肠上皮细胞cGMP/PKG2信号传导的关键效应因子的假设。目的2：验证PKG2在结肠上皮中具有屏障保护作用的假设。目的3：验证PKG2在结肠中具有肿瘤抑制作用的假设，以及临床相关PDE-5抑制剂的激活是一种有效的化学预防策略。本实验将利用Prkg2-/-小鼠和DSS/AOM和ApcMin/+小鼠肿瘤模型，测量PKG2信号及其被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方面的详细信息：(1)结肠上皮中PKG2依赖的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；(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实用性。我们项目的影响将是在结肠上皮中发现一种新的屏障保护信号通路，并证明该通路可以使用已经被证明对人类安全的药物靶向结肠癌化学预防。

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.