Colon cancer prevention with non-systemic PDE5 inhibitors

使用非全身性 PDE5 抑制剂预防结肠癌

• 批准号: 10484106
• 负责人: Darren D. Browning
• 金额: $ 19.17万
• 依托单位: TARGUT BIOTECHNOLOGIES INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10484106
• 关键词: Benign Prostatic Hypertrophy; Blood; Blood Circulation; Cancer Model; Cessation of life; Chemoprevention; Chemopreventive Agent; Clinical; Colon; Colon Carcinoma; Colorectal; Colorectal Cancer; Cyclic GMP; Data; Development; Diagnosis; Disease; Drug Interactions; Drug Kinetics; Epidemiology; Epithelial; Erectile dysfunction; Excretory function; Exposure to; Flushing; Future; Goals; Headache; Human; In Vitro; Intestines; Investigational Drugs; Libraries; Malignant Neoplasms; Measures; Metabolic; Metabolism; Modeling; Mus; Oral; Patients; Permeability; Persons; Pharmaceutical Preparations; Pharmacology; Population; Primary Prevention; Property; Pulmonary Hypertension; Reflux; Reporting; Risk; Role; Safety; Signal Transduction; Specificity; Stage at Diagnosis; Stream; Symptoms; Testing; Tumor Suppression; United States; absorption; analog; cancer chemoprevention; cancer diagnosis; carcinogenesis; colon cancer prevention; colon tumorigenesis; colorectal cancer prevention; colorectal cancer risk; design; epidemiology study; gastrointestinal epithelium; high risk; immunoregulation; inhibitor; mouse model; novel; phosphodiesterase V; pre-clinical; pre-clinical research; prevent; side effect; sildenafil; tadalafil; tumorigenesis; vardenafil

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.

在美国，今年将有大约5万人死于结直肠癌（CRC）