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（由申请人提供）：流行病学、实验和临床试验表明，非甾体类抗炎药 (NSAIDS) 具有显着的结肠癌 (CRC) 化学预防功效，但是，要实现适度降低 30-50% 的风险，治疗需要进行。这会使受试者遭受与 NSAIDS 相关的毒性的意外后果，例如溃疡、胃肠道出血、出血性中风等。这可能是特别有问题的。在没有表现出显着化学预防反应的受试者中，尚不清楚个体对化学预防的不同反应如何以及为何不同，可以想象，这些差异可能源于先天基因-环境相互作用（G X E；反映个体的遗传和生活方式因素），而这些相互作用可能呈现出独特的生物学特征。这些差异在性别特异性结直肠癌（女性近端病变、DNA 错配修复缺陷肿瘤等的患病率较高）中可能更为明显，且受遗传和环境因素的影响。 （饮食、肥胖、锻炼、饮酒和吸烟等）确实表明，女性对遗传和环境 CRC 危险因素的易感性发生了改变 [3]，这可能转化为对化学预防的反应。与男性相比，女性对 NSAIDS 的抗癌反应更强，尽管可能存在性别特异性生活方式因素的混杂因素，因此，为了提高 NSAIDS 相关化学预防的全人群风险效益，有必要进行改进。基于反映基因-环境相互作用影响的标记的群体选择过程，特别是与性别相关的正常结肠粘膜代表了基因-环境界面标记的强大资源，可以作为癌症风险的生物传感器。对于个性化 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体外模型（考虑到个体 G X E 相互作用的影响）在测量个体的NSAIDS 反应性。这些研究可以为早期 CRC 发展和化学预防的生物学调节因素提供一些见解，特别是在临床上，通过了解这些对化学预防的不同反应的复杂机制，我们有可能通过侵入性最小的方式制定个性化的筛查决策。考虑到即使我们可能使 CRC 风险加倍，绝大多数人 (~90%) 也永远不会发展为 CRC，但仍会承受潜在不必要的手术相关费用，这一点至关重要。因此，从生物学和公共卫生的角度来看，这一提议可能具有非常重要的意义。