Aberrant Crypt Foci as a Biomarker for Chemoprevention

描述（由申请人提供）：基于多种证据证明腺瘤是结直肠癌的前体病变，化学预防试验将腺瘤复发作为主要终点。这些试验需要大量的研究人群进行长时间的随访，并利用广泛的资源。因此，迫切需要确定一种替代终点生物标志物（SEB），它可以预测治疗效果，其验证将使更小、更短、成本更低的预防试验成为可能。异常隐窝病灶（ACF）是一个很有希望的SEB候选者。ACF是腺瘤和癌的推定前体，基于其与年龄相关的患病率、左侧的优势、不典型增生的频率以及与既往/当前肿瘤的关联。ACF可以通过放大色内窥镜在人类结直肠中检测和定量。结肠癌动物模型研究表明，ACF可作为一种SEB具有化学预防作用，非甾体抗炎药sulindac在日本受试者中显示可使ACF消退。迄今为止，关于美国人群ACF的数据有限，本提案的一个重要目的是在高风险人群中识别、量化和表征ACF。为此，我们建议在先前患有晚期结肠腺瘤或癌的患者中进行一项随机、安慰剂对照试验，评估阿司匹林单独使用和碳酸钙或二氟甲基鸟氨酸联合使用12个月。药物选择是基于令人信服的临床前和人体数据。主要研究终点将是12个月时左结肠ACF数与基线相比的百分比变化。将确定ACF特征（大小/形态、组织病理学），并评估ACF或正常粘膜的组织生物标志物。这些将包括药物靶点，即前列腺素E2和粘膜多胺水平，凋亡和增殖指数，EGFR的下游效应物，即环氧化酶-2 （COX-2）和细胞周期蛋白D1，以及基于初步数据的COX-2依赖性凋亡调节基因。还将进行ACF基因表达谱分析。为了确定ACF的自然病史，将在12个月的结肠镜检查中确定腺瘤复发，并对患者进行前瞻性随访，记录研究进入后36个月的结肠镜检查监测数据。

DESCRIPTION (provided by applicant): Chemoprevention trials have utilized adenoma recurrence as the primary endpoint based upon multiple lines of evidence establishing adenomas as precursor lesions of colorectal cancers. These trials require large study populations followed for extended time periods and utilize extensive resources. Accordingly, there is a critical need to identify a surrogate endpoint biomarker (SEB) that can predict treatment efficacy and whose validation would enable smaller, shorter-term and less costly prevention trials. A promising candidate SEB is the aberrant crypt foci (ACF). ACF are putative precursors of adenomas and carcinomas based upon their age-related prevalence, left-sided predominance, frequency of dysplasia, and association with prior/current neoplasia. ACF can be detected and quantified in the human colorectum using magnification chromoendoscopy. Studies in animal models of colon cancer indicate that ACF can serve as a SEB for chemopreventive efficacy and the NSAID sulindac was shown to regress ACF in Japanese subjects. To date, limited data are available on ACF in the U.S. population and an important aim of this proposal is to identify, quantify, and characterize ACF in a high risk population. To this end, we propose a randomized, placebo controlled trial in patients with prior advanced colonic adenomas or carcinomas evaluating aspirin alone and in combination with calcium carbonate or difluoromethylornithine over a 12 month period. Agent selection is based upon compelling preclinical and human data. The primary study endpoint will be the percent change in ACF number in the left colon at 12 month compared to baseline using magnifying chromoendoscopy. ACF characteristics (size/morphology, histopathology) will be determined and tissue biomarkers will be evaluated in ACF or normal mucosa. These will include drug targets, i.e., prostaglandin E2 and mucosal polyamine levels, apoptotic and proliferative indices, downstream effectors of EGFR, i.e., cyclooxygenase-2 (COX-2) and cyclin D1, and COX-2-dependent apoptotic regulatory genes based upon preliminary data. Gene expression profiling of ACF will also be performed. In an effort to determine the natural history of ACF, adenoma recurrence will be determined at the 12 month colonoscopy and patients will be followed prospectively to record surveillance colonoscopy data over a 36 month period post study entry.