Aberrant Crypt Foci as a Biomarker for Chemoprevention

描述（由申请人提供）：化学预防试验利用腺瘤复发作为主要终点，基于多条证据线，确立腺瘤为结直肠癌的前驱病变。这些试验需要大量的研究人群，并需要长时间的随访，并利用广泛的资源。因此，迫切需要鉴定一种替代终点生物标志物（SEB），其可以预测治疗功效，并且其验证将使得能够进行更小、更短期和成本更低的预防试验。一个有希望的候选SEB是异常隐窝病灶（ACF）。根据年龄相关的患病率、左侧优势、异型增生的频率以及与既往/当前肿瘤形成的相关性，ACF被认为是腺瘤和癌的前体。ACF可以检测和定量在人类结直肠使用放大色素内镜。结肠癌动物模型的研究表明，ACF可以作为化学预防功效的SEB，NSAID舒林酸显示出日本受试者的ACF消退。迄今为止，美国人群中ACF的数据有限，本提案的一个重要目的是识别、量化和表征高危人群中的ACF。为此，我们提出了一个随机的，安慰剂对照试验，在患者先前先进的结肠腺瘤或癌评估阿司匹林单独和联合碳酸钙或二氟甲基鸟氨酸超过12个月的时间。药物选择基于令人信服的临床前和人体数据。主要研究终点将是使用放大色素内镜检查的12个月时左结肠ACF数量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），并在ACF或正常粘膜中评价组织生物标志物。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，环氧合酶-2（考克斯-2）和细胞周期蛋白D1，以及基于初步数据的考克斯-2依赖性凋亡调控基因。还将进行ACF的基因表达谱分析。为了确定ACF的自然史，将在12个月结肠镜检查时确定腺瘤复发，并对患者进行前瞻性随访，以记录研究入组后36个月期间的监测结肠镜检查数据。

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.