Aberrant Crypt Foci as a Biomarker for Chemoprevention

异常隐窝病灶作为化学预防的生物标志物

• 批准号: 7691251
• 负责人: Frank A. Sinicrope
• 金额: $ 67.05万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7691251
• 关键词: Aberrant crypt foci; Age; Anabolism; Animal Model; Apoptosis; Apoptotic; Aspirin; Attenuated; Biochemical; Biological Markers; Calcium; Calcium Carbonate; Cancer Etiology; Carcinoma; Cell Proliferation; Cells; Cessation of life; Characteristics; Chemoprevention; Chemopreventive Agent; Clinical Research; Clinical Trials; Colon Carcinoma; Colonic Adenoma; Colonoscopy; Colorectal; Colorectal Adenoma; Colorectal Cancer; Colorectal Neoplasms; Cyclin D1; DL-alpha-Difluoromethylornithine; Data; Detection; Development; Dinoprostone; Dose; Drug Combinations; Drug Delivery Systems; Dysplasia; Enzymes; Epidemiology; Epidermal Growth Factor Receptor; Epithelium; Evaluation; Frequencies; Gene Expression Profiling; Genes; Histologic; Histology; Histopathology; Human; In Vitro; Intestinal Neoplasms; Japanese Population; Lasers; Left; Left colon; Lesion; Malignant Neoplasms; Mediating; Messenger RNA; Methods; Mitochondria; Morphology; Mucous Membrane; Mutation; Natural History; Neoplasms; Non-Steroidal Anti-Inflammatory Agents; Nuclear; Pathway interactions; Patients; Persons; Phase; Phase II Clinical Trials; Placebos; Polyamines; Polyps; Population; Population Study; Prevalence; Prevention; Prostaglandins; Proteins; Public Health; RNA amplification; Randomized; Randomized Controlled Trials; Recurrence; Regulator Genes; Relative (related person); Research Personnel; Resected; Resources; Risk; Safety; Side; Signal Transduction; Staging; Sulindac; Surrogate Endpoint; TNFRSF10B gene; TdT-Mediated dUTP Nick End Labeling Assay; Time; Tissues; Toxic effect; Treatment Efficacy; Treatment Protocols; Up-Regulation; Validation; adenoma; age related; base; cDNA Arrays; cancer prevention; caspase-3; cyclooxygenase 1; cyclooxygenase 2; drug efficacy; experience; follow-up; high risk; human data; improved; in vivo; indexing; inhibitor/antagonist; insight; mortality; neoplastic; placebo controlled study; pre-clinical; programs; randomized placebo controlled trial; receptor; rectal; treatment response; treatment trial; tumor growth

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.

描述(申请人提供)：化学预防试验以腺瘤复发为主要终点，根据多条证据确定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进行较长时间的跟踪，并利用大量资源。因此，迫切需要确定一种替代终点生物标记物(SEB)，它可以预测治疗效果，其验证将使更小、更短和更低成本的预防试验成为可能。异常隐窝病灶(ACF)是一种很有前途的SEB候选方法。根据其与年龄相关的患病率、左侧优势、不典型增生的频率以及与既往/当前肿瘤的关系，ACF可能是腺瘤和癌的先兆。使用放大显色内窥镜可以在人的结肠直肠中检测和定量ACF。在结肠癌动物模型中的研究表明，ACF可以作为化学预防效果的SEB，而非类固醇抗炎药舒林酸在日本受试者中被证明可以消退ACF。到目前为止，美国人群中有关ACF的数据有限，这项建议的一个重要目标是识别、量化和描述高危人群中的ACF。为此，我们建议在既往晚期结肠腺瘤或癌症患者中进行一项随机、安慰剂对照试验，评估阿司匹林单独以及与碳酸钙或二氟甲基鸟氨酸联合使用12个月的情况。选择药物是基于令人信服的临床前和人类数据。主要研究终点将是使用放大色素内窥镜检查12个月时左半结肠ACF数量与基线相比的百分比变化。将确定ACF的特征(大小/形态、组织病理学)，并对ACF或正常粘膜的组织生物标志物进行评估。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的下游效应因子，即环氧合酶-2(COX-2)和细胞周期蛋白D1，以及基于初步数据的COX-2依赖的凋亡调控基因。ACF的基因表达谱也将被执行。为了确定ACF的自然病史，腺瘤复发将在12个月的结肠镜检查中确定，患者将在研究进入后36个月内前瞻性地跟踪记录监视结肠镜检查数据。

项目成果

Efficacy of Difluoromethylornithine and Aspirin for Treatment of Adenomas and Aberrant Crypt Foci in Patients with Prior Advanced Colorectal Neoplasms.

二氟甲基鸟氨酸和阿司匹林治疗既往晚期结直肠肿瘤患者的腺瘤和异常隐窝病灶的疗效。

• DOI: 10.1158/1940-6207.capr-19-0167
• 发表时间: 2019
• 期刊: Cancer prevention research (Philadelphia, Pa.)
• 作者: Sinicrope,FrankA;Velamala,PruthviR;Song,LouisMWongKee;Viggiano,ThomasR;Bruining,DavidH;Rajan,Elizabeth;Gostout,ChristopherJ;Kraichely,RobertE;Buttar,NavtejS;Schroeder,KennethW;Kisiel,JohnB;Larson,MarkV;Sweetser,SethR
• 通讯作者: Sweetser,SethR

Celecoxib-induced apoptosis is enhanced by ABT-737 and by inhibition of autophagy in human colorectal cancer cells.

• DOI: 10.4161/auto.6.2.11124
• 发表时间: 2010-02
• 期刊: Autophagy
• 影响因子: 13.3
• 作者: Huang S;Sinicrope FA
• 通讯作者: Sinicrope FA

Beclin 1 and UVRAG confer protection from radiation-induced DNA damage and maintain centrosome stability in colorectal cancer cells.

• DOI: 10.1371/journal.pone.0100819
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Park JM;Tougeron D;Huang S;Okamoto K;Sinicrope FA
• 通讯作者: Sinicrope FA