Aspirin-PC for Chemoprevention of Colorectal Cancer

摘要 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 显著降低CRC发病率、死亡率和转移扩散。然而，长期使用这种药物是 由于易感受试者中胃肠道出血/溃疡的副作用而受到限制。的主要目标 这个修订的STTR第二阶段提案，由PI，Lenard M。Lichtenberger，博士，（教授 综合生物学和药理学，德克萨斯大学休斯顿健康科学中心）和小 业务，PLx制药公司，基于我们令人鼓舞的结果，在第一阶段，是使用细胞培养研究， 啮齿动物结肠直肠癌模型，以评估最近批准的新型阿司匹林的化学预防活性 药物，PL 2200（一种磷脂酰胆碱（PC）相关阿司匹林; 2013年1月向PLx Pharma发布NDA）， 在临床试验中证明，阿司匹林对胃肠道粘膜比传统阿司匹林更安全。我们将初步 评价单独的PL 2200（相对于未修饰的阿司匹林）对小鼠和人等基因 CRC细胞培养系。将与贝勒大学的Vinod Vijayan博士合作进行的研究 医学（Medicine），血小板功能的专家，将研究血小板在促进生长，侵入性， 活性和上皮间质转化（EMT）在结肠癌细胞，以及如何这些血小板诱导的亲， 阿司匹林-PC通过不可逆的考克斯-1抑制作用抑制致癌变化。为了深入了解 阿司匹林-PC/PL 2200的作用机制我们将比较测试的考克斯-1和考克斯-2抑制活性 制剂对CRC组织/下肠的血小板聚集/血栓烷生成和PGE 2浓度的影响 上皮细胞。随后将评估我们的试验药物影响异型增生生长的能力。 用葡聚糖硫酸钠（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的基因工程小鼠（GEM）模型-将在 我们的合作者，博士Kopetz和门特尔，在MD安德森癌症中心的实验室。胃肠道毒性的 将在上述动物模型中常规监测试验药物。我们还将研究PIK 3CA的作用 突变（发生在约20%的CRC患者中，并增强患者对阿司匹林的敏感性）。 阿司匹林-PC的化学预防功效，使用其中基因突变是 选择性表达。根据这些临床前研究，PLx Pharma Inc将进行一项试点研究 低剂量（81 mg）PL 2200的生产运行，并与PI和我们的 MDACC的同事设计了一项未来的临床试验，以评估低剂量PL 2200的长期使用（81 mg/天），并开发IND包装。

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.