Towards Development of an in vitro Assay to Personalize Colonic Chemoprevention

 描述（由申请人提供）：流行病学、实验和临床试验显示，非甾体抗炎药（NSAIDS）具有显著的结肠癌（CRC）化学预防益处。然而，为了实现适度的30-50%的风险降低，治疗需要广泛和长期传播。这使受试者暴露于非甾体抗炎药相关毒性的非预期后果，如溃疡、胃肠道出血、出血性中风等。这在未显示显著化学预防反应的受试者中可能特别成问题。个体如何以及为什么对化学预防反应不同尚不清楚。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;反映个体的遗传学和生活方式因素）引起的，其可能存在独特的生物学环境以影响NSAIDS敏感性。这些差异在性别特异性CRC中可能更明显（女性近端病变、DNA错配修复缺陷肿瘤等的患病率更高）。这是由遗传和环境因素（饮食，肥胖，运动，酒精和烟草使用等）的影响。事实上，我们的研究小组已经报道，女性对遗传和环境CRC风险因素的易感性发生了改变[3]，这可能会转化为对化学预防的反应性改变。一些流行病学研究确实表明，女性对NSAIDS的抗癌反应比男性更强，尽管可能存在性别特异性生活方式因素的混淆。因此，为了提高NSAIDS相关化学预防的全人群风险-获益，必须基于反映基因-环境相互作用影响的标记物（尤其是性别）改进人群选择过程。结肠粘膜表面正常，是基因-环境界面标记物的重要来源，可以作为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（考虑个体的G X E相互作用的影响）具有测量个体的NSAIDS响应性的巨大潜力。这些研究可以为早期CRC发展和化学预防的生物修饰剂提供一些见解，特别是与性别有关。在临床上，通过了解这些不同的化学预防反应的复杂机制，我们将有可能通过最低限度的侵入性测定（即直肠拭子）制定个性化的筛选决策。这是至关重要的，因为即使我们可能使CRC风险增加一倍，绝大多数（约90%）也永远不会发展为CRC，但会受到潜在的不必要的手术相关费用，疼痛和结肠镜检查的潜在并发症或NSAIDS的毒性的影响。因此，从生物学和公共卫生的角度来看，这一建议可能具有非常重要的意义。

 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.