Safer Approaches to CRC Chemoprevention

更安全的 CRC 化学预防方法

基本信息

批准号：
9261808
负责人：
Chinthalapally V. Rao
金额：
$ 45.86万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-15 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9261808
关键词：
Adoptive Transfer Adverse effects American Anti-Inflammatory Agents Anti-inflammatory Arachidonate 5-Lipoxygenase Arachidonic Acids Arterial Fatty Streak Aspirin Atherosclerosis Azoxymethane Biological Assay Biological Models Bone Marrow C57BL/6 Mouse Cancer Etiology Cancer Model Cardiac Cardiovascular system Chemopreventive Agent Chronic Clinical Clinical Trials Colon Adenocarcinoma Colon Carcinoma Colonic Neoplasms Colorectal Cancer Coxibs Data Development Diagnosis Dinoprostone Dose Early Intervention Eicosanoids Enzyme Kinetics Epidemiology Epoprostenol Exposure to Female Health High Fat Diet Inbred F344 Rats Individual Laboratories Lipoxygenase Inhibitors Modification Mus Outcome Outcomes Research Patients Pharmaceutical Preparations Pharmacodynamics Pre-Clinical Model Prevention Preventive Property Prostaglandin Inhibition Prostaglandin-Endoperoxide Synthase Rattus Research Research Design Risk Risk Reduction Role Safety Serum Source Testing Thrombosis Tissue Sample Tissues Toxic effect Tumorigenicity atorvastatin base cancer chemoprevention cancer prevention cancer risk cancer therapy cardiovascular risk factor celecoxib colorectal cancer prevention combinatorial cyclooxygenase 1 cyclooxygenase 2 effective therapy efficacy study experimental study gastrointestinal high risk improved in vivo inhibitor/antagonist macrophage male mortality mouse PGE synthase 1 novel novel therapeutics prevent response tissue biomarkers transcriptomics tumor tumor growth tumorigenic

项目摘要

Project Summary The major purpose of this proposed research is to develop mechanistically based, effective, and safer agents for colorectal cancer (CRC) chemoprevention. Every year, about 150,000 Americans are diagnosed with colorectal cancer (CRC), the second leading cause of cancer-related mortality in the US. About 1.35 million new CRC cases are diagnosed worldwide, highlighting that CRC is a major health problem. Evidence from our group and others suggests that NSAIDs and select COX-2 inhibitors show significant inhibitory effects in preclinical models and patients with CRC, but these inhibitors are also associated with gastrointestinal (GI) toxicity and cardiovascular (CV) risk. Reasons for these risks include increased 5-LOX metabolites and reduced PGI2 synthesis. Thus, selectively targeting microsomal PG Synthase-1 (mPGES-1) and 5-LOX would block the protumorigenic PGE2/prothrombotic LTs, but spare the PGI2. This approach is ideal for developing efficient and safer CRC chemopreventive agents. Toward this end, through high-throughput and enzyme kinetics assays and short- term in vivo efficacy studies, we have discovered a novel dual mPGES-1 /5-LOX inhibitor, CDPDPA. In this proposal, we seek to further develop CDPDPA for CRC chemoprevention. We have designed the research strategies to assess the pharmaco-dynamic dose-response efficacy, understand the role of mPGES-1/5- LOX, improve efficacy and safety through combinatorial approaches, and evaluate CV risk, if any, of CDPDPA compared with COX-2 inhibitor. We have assembled a team with expertise in CRC chemoprevention and cardivascular research to undertake following aims. 1). Determine whether targeting both mPGES-1 and 5-LOX with CDPDPA is efficacious in AOM-induced rat colon adenocarcinoma treatment; 2) Determine the source and relative contribution of mPGES-1 and 5-LOX to colon tumor developmen;t 3). Determine whether combinational targeting of mPGES-1/5-LOX with statin would improve the colon tumor inhibition efficacy and reduce cardiovascular side effects compared with celecoxib, and; 4). Determine the potential CV risk, if any, of long-term administration of CDPDPA compared with Celecoxib in LDLr-/-ApoB100/100 mice. The completion of this project will significantly improve the safety and efficacy of this novel drug for the prevention and treatment of CRC.

项目概要这项研究的主要目的是开发基于机械的、有效的和用于结直肠癌（CRC）化学预防的更安全药物。每年，约有 150,000 名美国人被诊断患有结直肠癌 (CRC)，这是第二大癌症美国癌症相关死亡的原因。全球约有 135 万新诊断的 CRC 病例，强调结直肠癌是一个主要的健康问题。我们小组和其他人的证据表明，非甾体抗炎药并选择 COX-2 抑制剂在临床前模型和 CRC 患者中显示出显着的抑制作用，但这些抑制剂也与胃肠道 (GI) 毒性和心血管 (CV) 风险相关。这些风险的原因包括 5-LOX 代谢物增加和 PGI2 合成减少。因此，选择性靶向微粒体 PG Synthase-1 (mPGES-1) 和 5-LOX 将阻断促肿瘤发生 PGE2/促血栓 LT，但保留 PGI2。这种方法非常适合开发高效且更安全的 CRC 化学预防剂。为此，通过高通量和酶动力学测定以及短期在体内功效研究中，我们发现了一种新型的双重 mPGES-1 /5-LOX 抑制剂 CDPDPA。在这个根据提案，我们寻求进一步开发用于 CRC 化学预防的 CDPDPA。我们设计了研究评估药效剂量反应功效的策略，了解 mPGES-1/5- 的作用 LOX，通过组合方法提高疗效和安全性，并评估 CV 风险（如果有） CDPDPA与COX-2抑制剂比较。我们组建了一支具有 CRC 专业知识的团队化学预防和心血管研究致力于实现以下目标。 1).判断是否定位 mPGES-1 和 5-LOX 联合 CDPDPA 对 AOM 诱导的大鼠结肠腺癌有效治疗; 2) 确定mPGES-1和5-LOX的来源和对结肠肿瘤的相对贡献发展；t 3)。确定 mPGES-1/5-LOX 与他汀类药物的联合靶向是否会改善与塞来昔布相比，结肠肿瘤抑制功效和降低心血管副作用； 4）。确定与塞来昔布相比长期服用 CDPDPA 的潜在 CV 风险（如果有）在 LDLr-/-ApoB100/100 小鼠中。该项目的完成将显着提高药物的安全性和有效性这种新药用于预防和治疗结直肠癌。