Colon cancer prevention with non-systemic PDE5 inhibitors

由于晚期癌症，今年美国约有5万人死于结直肠癌（CRC）。 诊断阶段，治疗在很大程度上无效。因此，CRC的一级预防非常重要。 对于高危患者来说，CRC需要化学预防剂，但尚未批准 用于此目的。广泛的临床前和流行病学证据显示， 磷酸二酯酶-5抑制剂（PDE 5i）用于CRC化学预防。PDE 5i应用的障碍包括 全身给药引起的众多副作用和药物间相互作用， 健康人群中的依从性。我们的目标是开发新的肠道靶向PDE 5i用于CRC 高危人群的化学预防。 我们的中心假设是，西地那非的极性类似物将成为理想的非全身性药物， 用于人类CRC的主要化学预防的药物。我们的目标是（1）获得详细的 关于丙二酰-和硼酰-西地那非体外药代动力学特性的信息，以及（2）确定 这些类似物是否可以预防散发性CRC小鼠模型中的结肠癌。我们将测试我们的中央 假设，从而通过完成以下目标来实现本项目的目标： 目标1.检验西地那非极性类似物作为肠上皮靶向PDE 5i的假设。 目标2.验证西地那非极性类似物对小鼠结肠癌的抑制作用。 通过在临床前CRC模型中提供详细的药代动力学信息和原理证明， 该项目的科学影响将是为我们的极性PDE 5i类似物的进一步开发扫清道路， 用于CRC的主要化学预防的同类药物。

Approximately 50,000 people will die from colorectal cancer (CRC) in the United States this year due to the late stage at diagnosis where treatments are largely ineffective. Primary prevention of CRC is therefore very important for high-risk patients. Chemoprevention agents are needed for CRC but nothing has been approved for this purpose. Extensive preclinical and epidemiological evidence show great promise for repurposing phosphodiesterase-5 inhibitors (PDE5i) for CRC chemoprevention. Barriers to this application of PDE5i include the numerous side effects and drug-drug interactions resulting from systemic delivery that would reduce compliance in an otherwise healthy population. Our goal is to develop novel gut-targeted PDE5i for CRC chemoprevention in people at high risk. Our central hypothesis is that polar analogs of sildenafil will make ideal non-systemic agents for developing into drugs for the primary chemoprevention of CRC in humans. Our objectives are (1) To gain detailed information about the pharmacokinetic properties of malonyl- and boronyl-sildenafil in vitro, and (2) to determine whether these analogs can prevent colon cancer in a mouse model of sporadic CRC. We will test our central hypothesis and thereby accomplish the objectives of this project by completing the following aims: Aim 1. Test the hypothesis that polar analogs of sildenafil behave as gut-epithelium targeted PDE5i. Aim 2. To test the hypothesis that polar analogs of sildenafil can inhibit colon cancer in mice. By providing detailed pharmacokinetic information and proof of principle in a preclinical CRC model, our project's scientific impact will be to clear the path for further development of our polar PDE5i analogs as first in class drugs for the primary chemoprevention of CRC.