Towards Development of an in vitro Assay to Personalize Colonic Chemoprevention

开发个性化结肠化学预防的体外测定

• 批准号: 9039559
• 负责人: Hemant K. Roy
• 金额: $ 8.7万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9039559
• 关键词: Accounting; Adenocarcinoma; Adenomatous Polyps; Advisory Committees; Affect; Age; Alcohol consumption; Apoptosis; Aspirin; Benefits and Risks; Benign; Biological; Biological Assay; Biological Markers; Biopsy; Biosensor; Brain hemorrhage; CASP3 gene; Cancer Model; Cell Culture Techniques; Chemoprevention; Chemopreventive Agent; Clinical; Clinical Trials; Collaborations; Colon Carcinoma; Colonoscopy; Colorectal Cancer; DNA lesion; Data; Detection; Development; Diet; Doctor of Philosophy; Environment; Environmental Risk Factor; Enzymes; Epidemiologic Studies; Epidemiology; Etiology; Excision; Exercise; Experimental Models; Female; Fostering; Future; Gastrointestinal Hemorrhage; Gender; Genes; Genetic; Genetic Polymorphism; Goals; Growth; Health; High Prevalence; In Vitro; Individual; Lesion; Malignant - descriptor; Malignant Neoplasms; Measures; Mismatch Repair; Modeling; Molecular; Molecular Biology; Molecular Genetics; Monitor; Mucous Membrane; Neoplasms; Non-Steroidal Anti-Inflammatory Agents; Obesity; Pain; Patients; Peer Review; Pharmaceutical Preparations; Pharmacotherapy; Polypectomy; Population; Populations at Risk; Predisposition; Prevalence; Preventive; Preventive service; Process; Public Health; Publications; Rattus; Reading; Regimen; Reporting; Resources; Risk; Risk Factors; Risk Reduction; Risk-Benefit Assessment; Rodent; Rodent Model; Sampling; Staging; Swab; Time; Tissues; Tobacco use; Toxic effect; Translating; Tumor-Suppressor Gene Inactivation; Ulcer; Unnecessary Procedures; Woman; adenoma; base; beta catenin; biomarker development; cancer risk; carcinogenesis; case control; celecoxib; colorectal cancer prevention; cost; cyclooxygenase 2; drug sensitivity; gene environment interaction; hazard; improved; in vitro Assay; in vitro Model; in vitro testing; in vivo; insight; interest; lifestyle factors; male; men; multidisciplinary; neoplastic; rectal; response; screening; success; tumor

 DESCRIPTION (provided by applicant): Nonsteroidal anti-inflammatory drugs (NSAIDS) have marked colon cancer (CRC) chemopreventive benefits as shown in epidemiological, experimental and clinical trials. However, to achieve a modest 30-50% risk reduction, the therapy needs to be extensive and spread over a long period. This exposes subjects to unintended consequences of NSAIDS-related toxicity such as ulcers, GI bleeding, hemorrhagic strokes etc. This may be particularly problematic in subjects displaying no significant chemopreventive response. How and why individuals respond to chemoprevention differently is unclear. It is conceivable that these differences may arise from innate gene-environment interactions (G X E; reflecting genetics and lifestyle factors of an individual) that may present unique biological milieu to affect NSAIDS sensitivity. These differences may be more noticeable in gender specific CRC (with women having higher prevalence of proximal lesions, DNA mismatch repair deficient tumors etc.) that are influenced by both genetic and environmental factors (diet, obesity, exercise, alcohol and tobacco use etc.). Indeed, our group has reported that women have altered susceptibility to both genetic and environmental CRC risk factors [3] which may possibly translate into altered responsiveness to chemoprevention. Some epidemiological studies do suggest that women have a stronger anti-cancer response to NSAIDS then men, although there may be confounding from gender specific lifestyle factors. To enhance population-wide risk-benefit of NSAIDS related chemoprevention, it is therefore essential to improve the population selection process based on markers that reflect influence of gene-environment interactions especially with respect to gender. Opportunely uninvolved normal appearing colonic mucosa represents a powerful resource for the gene-environment interface markers that can act as biological sensors for cancer risk. Therefore, for personalized NSAIDS chemopreventive risk-benefit analysis, in vitro model of colonic mucosal cell cultures developed from colonic tissue (that take into consideration influences of the individual's G X E interactions) have a great potential for gaging individual's NSAIDS responsiveness. These studies can provide some insights into the biological modifiers of early CRC development and chemoprevention especially in relation to gender. Clinically, by understanding the intricate mechanisms of these differential responses to chemoprevention, we would potentially develop individualized screening decisions through a minimally intrusive assay (i.e. rectal swab). This is critical given that even if we may double CRC risk, the vast majority (~90%) will never develop CRC yet are subjected to potentially unnecessary procedure associated costs, pain and potential complications of colonoscopy or the toxicity of NSAIDS. Thus, this proposal could potentially be highly significant from both a biological and public health perspective.

 描述（由适用提供）：非甾体类抗炎药（NSAIDS）具有明显的结肠癌（CRC）化学预防益处，如流行病学，实验和临床试验所示。但是，为了实现适度的30-50％的风险降低，该治疗需要长时间广泛并分布。这暴露于NSAIDS相关毒性的意外后果，例如溃疡，GI出血，出血性中风等。这在没有明显的化学预防反应的受试者中尤其有问题。个人如何以及为什么对化学预防的反应不同。可以想象，这些差异可能是由先天基因环境相互作用（G x e；反映一个个体的遗传学和生活方式因素）可能带来独特的生物环境来影响NSAID敏感性的。这些差异在性别特定的CRC中可能更明显（女性患有近端病变的患病率更高，DNA不匹配修复缺乏肿瘤等）受遗传和环境因素（饮食，肥胖，运动，酒精和烟草的使用等）的影响）。确实，我们的小组报告说，妇女对遗传和环境CRC风险因素的敏感性改变了[3]，这可能会转化为对化学预防的反应性改变。一些流行病学研究的确表明，女性对NSAID的反应比男性具有更强的抗癌反应，尽管从性别特定的生活方式因素中可能会有混淆。为了增强与NSAID相关的化学预防的人口范围的风险效益，因此，基于反映基因环境相互作用的标志物，特别是在性别方面的影响。出现循环的非正常出现结肠粘膜是基因环境界面标记的强大资源，可以充当癌症风险的生物传感器。因此，对于个性化的NSAIDS化学预防风险效益分析，从结肠组织开发的结肠粘膜细胞培养物的体外模型（考虑到个人的G x e相互作用的影响）具有巨大的潜力，可增强个人的NSAID响应能力。这些研究可以为早期CRC发育和化学预防的生物学修饰剂提供一些见解，尤其是与性别有关。在临床上，通过了解这些对化学预防的差异反应的复杂机制，我们将通过最小侵入性的测定法（即直肠拭子）制定个性化的筛查决策。至关重要的是，即使我们可能会加倍CRC风险，绝大多数（〜90％）永远不会发展CRC，但仍会受到潜在的不必要的程序相关的成本，疼痛和结肠镜检查的潜在并发症或NSAID的毒性。从生物学和公共卫生的角度来看，这一提议可能非常重要。