Aspirin-PC for Chemoprevention of Colorectal Cancer

阿司匹林-PC 用于结直肠癌的化学预防

基本信息

批准号：
9932670
负责人：
LENARD M LICHTENBERGER
金额：
$ 6.5万
依托单位：
PLX OPCO, INC.
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-03 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9932670
关键词：
Acute Affect Animal Model Antineoplastic Agents ApcMin/+ mice Apoptosis Aspirin Award Azoxymethane Biological Models Biology Blood Platelets Businesses Cancer Cell Growth Cancer Center Cancer Etiology Cancer Model Carcinogens Cell Culture Techniques Cessation of life Chemoprevention Chemopreventive Agent Chronic Clinical Research Clinical Trials Collaborations Colon Colon Carcinoma Colonic Adenoma Colorectal Cancer Consultations Consumption Cyclic GMP Data Dinoprostone Distal Division of Cancer Prevention Doctor of Philosophy Dose Drug usage Elderly Epithelial Evaluation FDA approved Formulation Future Gastroenterology Gastrointestinal Hemorrhage Gastrointestinal tract structure Gene Mutation Generations Genetic Engineering Genetically Engineered Mouse Goals Grant Growth Hawks Head Health Sciences Human In Vitro Incidence Laboratories Lead Lecithin Lipids Malignant Neoplasms Medical Oncology Medicine Mesenchymal Meta-Analysis Modeling Monitor Mucous Membrane Mus Mutation Names Oils PIK3CA gene PTGS2 gene Parents Patients Pharmaceutical Preparations Pharmacology Phase Platelet aggregation Platelet-Derived Growth Factor Population Sciences Preparation Publications Publishing Rattus Recommendation Risk Rodent Rodent Model Role Running Safety Series Small Business Technology Transfer Research Sodium Dextran Sulfate Testing Texas Thromboxanes Tissues Toxicity Tests Ulcer Universities Vascular Endothelial Growth Factors base cancer cell capsule carcinogenicity college colon cancer cell line colon cancer patients colon dysplasia colon growth colorectal cancer risk cyclooxygenase 1 design drug testing epidemiology study gastrointestinal gastrointestinal epithelium improved in vitro Model in vivo Model insight loss of function meetings mid-career faculty migration mortality mouse model novel novel therapeutics patient population phase 1 study phase 2 study platelet function preclinical study predictive marker professor prospective response selective expression side effect soy tumor progression

项目摘要

ABSTRACT Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the U.S. Based on numerous epidemiological studies and recent prospective clinical trials, the use of daily aspirin is associated with a significant reduction in CRC incidence, deaths and metastatic spread. However, the chronic use of this drug is limited due to the side-effects of gastrointestinal bleeding/ulceration in susceptible subjects. The main goal of this revised STTR Phase II proposal, developed by the PI, Lenard M. Lichtenberger, PhD, (Professor of Integrative Biology & Pharmacology, The University of Texas Health Science Center at Houston) and the small business, PLx Pharma Inc, based upon our encouraging results in Phase I, is to use cell culture studies and rodent colorectal cancer models to evaluate the chemopreventive activity of a recently approved novel aspirin drug, PL2200 (a phosphatidylcholine (PC)-associated aspirin; NDA issued to PLx Pharma in 01/ 2013), that has been documented in clinical trials to be safer to the GI mucosa than traditional aspirin. We will initially evaluate PL2200 (vs unmodified aspirin) alone on proliferation and apoptosis of mouse and human isogenic CRC cell culture lines. Studies to be performed in collaboration with Dr. Vinod Vijayan from Baylor College of Medicine (BCM), an expert on platelet function, will study the role of platelets in promoting growth, invasive activity and Epithelial-Mesenchymal Transition (EMT) in colon cancer cells and how these platelet-induced pro- carcinogenic changes are inhibited by Aspirin-PC via irreversible COX-1 inhibition. To gain insight into the mechanism of action of Aspirin-PC/PL2200 we will compare the COX-1 and COX-2 inhibitory activity of the test formulations on platelet aggregation/ thromboxane generation and PGE2 concentration of CRC tissue/lower gut epithelium, respectively. This will be followed by evaluating our test drugs ability to affect the dysplastic growth of colonic mucosa of APCMin/+ mice and APC-deficient rats challenged with dextran sodium sulfate (DSS) to induce colonic adenomas and genetic engineered mouse (GEM) models of CRC - to be performed in the laboratory of our collaborators, Drs Kopetz and Menter, at MD Anderson Cancer Center. The GI toxicity of the test-drugs will routinely be monitored in the above animal models. We will also study the role of PIK3CA mutation (which occurs in ~20% of CRC patients and enhances the patient's sensitivity to aspirin) on the chemopreventive efficacy of Aspirin-PC, using the isogenic CRC cell lines where the gene mutation is selectively expressed. Based upon these pre-clinical studies, PLx Pharma Inc will perform a pilot manufacturing run of low-dose (81mg) PL2200 and develop a strategy in consultation with the PI and our colleagues at MDACC to design a future clinical trial to evaluate the chronic use of low-dose PL2200 (81 mg/day) on “at-risk” CRC patients and develop an IND package.

抽象的根据大量研究，结直肠癌 (CRC) 是美国癌症相关死亡的第三大原因流行病学研究和最近的前瞻性临床试验表明，每日服用阿司匹林与结直肠癌的发病率、死亡率和转移扩散显着降低，但长期使用这种药物会产生副作用。由于易感受试者胃肠道出血/溃疡的副作用而受到限制。这个修订后的 STTR 第二阶段提案由 PI Lenard M. Lichtenberger 博士（综合生物学与药理学，德克萨斯大学休斯顿健康科学中心）和小型 PLx Pharma Inc 的业务，基于我们在第一阶段的令人鼓舞的结果，是利用细胞培养研究和啮齿动物结直肠癌模型，用于评估最近批准的新型阿司匹林的化学预防活性药物 PL2200（一种磷脂酰胆碱 (PC) 相关阿司匹林；2013 年 1 月向 PLx Pharma 发布的新药申请 (NDA)），临床试验表明，它比传统的阿司匹林对胃肠道粘膜更安全。评估单独的 PL2200（与未修饰的阿司匹林相比）对小鼠和人类同基因的增殖和凋亡的影响 CRC 细胞培养系将与贝勒学院的 Vinod Vijayan 博士合作进行。血小板功能专家医学（BCM）将研究血小板在促进生长、侵袭性等方面的作用结肠癌细胞中的活性和上皮间质转化 (EMT) 以及这些血小板如何诱导促阿司匹林-PC 通过不可逆的 COX-1 抑制来抑制致癌变化。 Aspirin-PC/PL2200的作用机制我们将比较COX-1和COX-2抑制活性的测试制剂对 CRC 组织/下肠的血小板聚集/血栓素生成和 PGE2 浓度的影响随后将分别评估我们的测试药物影响发育不良生长的能力。用右旋糖酐硫酸钠 (DSS) 激发 APCMin/+ 小鼠和 APC 缺陷大鼠的结肠粘膜诱导结肠腺瘤和 CRC 基因工程小鼠 (GEM) 模型 - 将在我们的合作者 Kopetz 博士和 Menter 博士在 MD 安德森癌症中心的实验室研究了该药物的胃肠道毒性。我们还将在上述动物模型中常规监测试验药物的作用。突变（约 20% 的 CRC 患者发生这种突变，并增强患者对阿司匹林的敏感性）使用基因突变为的同基因 CRC 细胞系，阿司匹林-PC 的化学预防功效根据这些临床前研究，PLx Pharma Inc 将进行试点。低剂量 (81mg) PL2200 的生产运行，并与 PI 和我们的协商制定策略 MDACC 的同事设计了一项未来的临床试验来评估低剂量 PL2200 的长期使用（81 毫克/天）用于“高危”CRC 患者并开发 IND 包。