Aspirin-PC for Chemoprevention of Colorectal Cancer

摘要 结直肠癌(CRC)是美国与癌症相关的死亡的第三大原因。 流行病学研究和最近的前瞻性临床试验表明，每天服用阿司匹林与 显著降低了结直肠癌的发病率、死亡率和转移扩散。然而，这种药物的长期使用是 由于易感受试者的胃肠道出血/溃疡的副作用而受到限制。的主要目标是 这一修订的STTR第二阶段提案由PI Lenard M.Lichtenberger博士( 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 商业，PLx Pharma Inc.，基于我们在第一阶段令人鼓舞的结果，将使用细胞培养研究和 评价新近批准的一种新型阿司匹林的化学预防活性的啮齿动物结直肠癌模型 药物，PL2200(一种磷脂酰胆碱(PC)相关的阿司匹林；2013年1月向PLx Pharma颁发的NDA)， 已经在临床试验中证明对胃肠道粘膜比传统的阿司匹林更安全。我们最初会 PL2200(与未修饰的阿司匹林)单独作用对小鼠和人同基因细胞增殖和凋亡的影响 结直肠癌细胞培养株。将与贝勒学院的Vinod Vijayan博士合作进行研究 医学(BCM)是一家研究血小板功能的专家，他将研究血小板在促进生长、侵袭性 结肠癌细胞的活性和上皮-间充质转化(EMT)以及这些血小板如何诱导促进 阿司匹林-PC通过不可逆地抑制COX-1而抑制致癌变化。要深入了解 阿司匹林-PC/PL2200的作用机制比较环氧合酶-1和环氧合酶-2的抑制活性 结直肠癌组织/下肠道血小板聚集/血栓素生成及前列腺素E_2浓度的研究 上皮细胞。接下来将评估我们的测试药物影响发育不良的能力。 葡聚糖硫酸钠(DSS)对APCMin/+小鼠和APC缺陷大鼠结肠黏膜的影响 诱导结肠腺瘤和基因工程小鼠(GEM)结直肠癌模型-在 我们的合作者Kopetz博士和Menter博士在MD Anderson癌症中心的实验室。胃肠道毒性的研究 在上述动物模型中，测试药物将进行常规监测。我们还将研究PIK3CA的作用 基因突变(发生在约20%的结直肠癌患者中，并增强患者对阿司匹林的敏感性) 阿司匹林-PC的化学预防作用--使用基因突变所在的等基因CRC细胞系 有选择地表达。基于这些临床前研究，PLx Pharma Inc.将进行一项试点 低剂量(81 Mg)PL2200的生产运行，并与PI和OUR协商制定战略 MDACC的同事们设计了一项未来的临床试验，以评估长期使用低剂量PL2200(81 Mg/天)，并开发IND包。

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.