LFA-9 (mPGES-1/5-LOX Inhibitor): Preclinical Studies to Support a Clinical Trial,

LFA-9（mPGES-1/5-LOX 抑制剂）：支持临床试验的临床前研究，

• 批准号: 10794912
• 负责人: David McCormick
• 金额: $ 41.87万
• 依托单位: IIT RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-17 至 2024-03-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10794912
• 关键词: APC gene; Abdominal Pain; Adverse effects; Affect; Anti-Inflammatory Agents; ApcMin/+ mice; Arachidonate 5-Lipoxygenase; Aspirin; Biological Assay; Canis familiaris; Cardiovascular system; Cells; Chemoprevention; Chemopreventive Agent; Chronic; Clinical Trials; Colon; Colonic Neoplasms; Colorectal Cancer; Coronary heart disease; Development; Diarrhea; Disease; Docking; Dominant Genetic Conditions; Dose; Drug Kinetics; Duodenum; Epoprostenol; Event; Familial Adenomatous Polyposis Syndrome; Gene Mutation; Genes; Head; Hepatocyte; Hereditary Disease; High Pressure Liquid Chromatography; Human; Ibuprofen; In Vitro; Inflammatory; Intestinal Neoplasms; Left; Lipoxygenase Inhibitors; Mammalian Cell; Metabolism; Methods; Microsomes; Molecular; Mus; Mutation; Naproxen; Nervous System Physiology; Oral; Oral Administration; PTGS2 gene; Patients; Precancerous Polyp; Prostaglandin Production; Prostaglandins; Prostaglandins I; Rattus; Recording of previous events; Recovery; Rectum; Research Personnel; Risk; Rodent; Small Intestinal Neoplasm; Techniques; Testing; Toxic effect; Work; adenoma; analog; appropriate dose; autosome; cardiovascular risk factor; celecoxib; colorectal cancer prevention; cyclooxygenase 1; cytokine; efficacy study; in silico; in vivo; lead candidate; lifetime risk; micronucleus; nonhuman primate; preclinical study; rectal; screening; side effect; targeted agent; thrombotic

Familial Adenomatous Polyposis (FAP) is a rare inherited disease which results from an autosomal dominant genetic alteration in the adenomatous polyposis coli (APC) gene. Patients with this disease develop hundreds to thousands of pre-cancerous polyps (adenomas) in the duodenum, colon and rectum. Left untreated, patients have almost 100% lifetime risk of developing colorectal cancer (CRC). There is unequivocal evidence of chemopreventive efficacy in CRC with anti-inflammatory agents that exert their effects through COX-2 inhibition (e.g. aspirin, ibuprofen, naproxen and celecoxib), however chronic use of these agents is associated with an increased risk of GI toxicity. Moreover, agents that target COX-2 have been implicated in cardiovascular (CV) and thrombotic events for patients with a baseline history of atherosclerotic heart disease. Several investigators have shown the increased CV risk to be associated with reduced levels of prostaglandin I2 (PGI2 or prostacyclin) and increased levels of 5-lipoxygenase (5-LOX) metabolites. Hence, Dr. Rao and others hypothesize that agents that spare PGI2 and selectively block production of prostaglandin E-2 (PGE2) and 5-LOX metabolites should prove promising in the prevention of CRC. One such agent, licofelone, targets microsomal prostaglandin E Synthase-1 (mPGES-1) and 5-LOX, and suppresses small intestinal and colonic tumor formation in the ApcMin/+ mouse at doses that are devoid of overt toxicity. Inhibition of intestinal tumors was also associated with decreases in inflammatory cytokines and COX and 5-LOX activities. Furthermore, in clinical trials for OA, the common side effects with licofelone were mild (abdominal pain and diarrhea). In silico molecular docking techniques and in vitro and in vivo screening methods have been employed to identify biologically active licofelone analogs. The lead candidate of this effort, LFA- 9, has been selected for further development. The main objective of this Task Order RFP is to conduct preclinical studies with LFA-9 to support its use in a clinical trial.

家族性腺瘤性息肉病（FAP）是一种罕见的遗传性疾病，由大肠腺瘤性息肉病（APC）基因的常染色体显性遗传改变引起。患有这种疾病的患者在十二指肠、结肠和直肠中会出现成百上千的癌前息肉（腺瘤）。如果不及时治疗，患者一生中患结直肠癌（CRC）的风险几乎为100%。