Chemoprevention of Colitis-Associated Neoplasia by 5-ASA

描述（由申请人提供）： 虽然溃疡性结肠炎患者发生结直肠癌的风险比一般人群显著增加，但很少有人关注针对这一高危人群的化学预防干预措施的发展。此外，结肠镜检查不能可靠地检测溃疡性结肠炎患者的早期病变，特别是扁平发育不良。通过该组的初步数据提供了拟定研究的依据，这些数据证明了5-氨基水杨酸（5-阿萨）（治疗人类结肠炎的一线疗法）在诱导结肠炎前给药时抑制小鼠中AOM/DSS诱导的结肠炎相关发育不良的多重性的能力。最有趣的是息肉样（大小减少）和扁平（多样性减少）发育不良对药物治疗的潜在差异反应。这些数据表明，扁平和息肉样发育不良可能对5-阿萨暴露的反应不同，这些病变亚型可能通过独立的遗传途径产生。该组的最新数据证实，在诱导DSS后给予5-阿萨可抑制结肠炎相关病变;这是一种具有临床意义的治疗方案。本研究的总体目标是通过将新的成像技术与遗传分析和生物信息学的最新进展相结合，获得对5-阿萨对AOM/DSS诱导的结肠炎相关结肠直肠癌的化学预防活性的新见解。该实验的假设是5-阿萨通过不同的遗传途径改变息肉样和扁平病变的生长，从而有效抑制结肠炎相关瘤形成。将在具体目标1中检查5-阿萨最佳剂量降低结肠发育不良的多样性和大小以及相关炎症的能力。这些数据将通过使用MRI、结肠镜检查和全身荧光成像与生物活化探针进行补充，以监测炎症程度（结肠壁厚度）以及息肉样和扁平病变随时间的生长。在特定目标3中，将采用基于微阵列的分析来比较和对比炎症非肿瘤性粘膜与息肉样和扁平发育不良的基因表达谱，以及鉴定暴露于5-阿萨后每种组织类型中表达改变的基因。这些临床前分析的结果有望增强我们对息肉样和扁平结肠炎相关发育不良的遗传基础的理解，并促进结肠恶性肿瘤风险增加的溃疡性结肠炎患者的化学预防方案的开发。公共卫生相关性：由于结肠镜检查不能可靠地检测溃疡性结肠炎患者的早期结肠癌，因此非常需要为这一高危人群开发癌症预防治疗。拟议的小鼠研究结果可能导致5-阿萨用于癌症预防，并显著影响炎症性肠病患者临床管理未来指南的建立。

DESCRIPTION (provided by applicant): Although ulcerative colitis patients are at a significantly increased risk of developing colorectal cancer as compared to the general population, little attention has been given to the development of a chemopreventive intervention for this high-risk population. Furthermore, colonoscopies fail to reliably detect early lesions, in particular flat dysplasias, in ulcerative colitis patients. Rationale for the proposed study is provided by preliminary data from this group that demonstrate the ability of 5-aminosalicylic acid (5-ASA), the first-line therapy for the treatment of human colitis, to inhibit the multiplicity of AOM/DSS-induced colitis-associated dysplasias in mice when given prior to the induction of colitis. Most interesting was the potential differential response of polypoid (reduction in size) and flat (decrease in multiplicity) dysplasias to drug therapy. These data suggest that flat and polypoid dysplasias may respond differently to 5-ASA exposure and that these lesion subtypes may arise via independent genetic pathways. More recent data from this group confirm that 5-ASA can inhibit colitis-associated lesions when administered after the induction of DSS; a schedule of clinical relevance. The overall goal of this study is to gain new insight into the chemopreventive activity of 5-ASA against AOM/DSS-induced colitis-associated colorectal cancer by combining novel imaging techniques with state- of-the-art advances in genetic profiling and bioinformatics. The hypothesis of the proposed experimentation is that 5-ASA effectively inhibits colitis-associated neoplasia by altering the growth of polypoid and flat lesions via distinct genetic pathways. The ability of an optimal dose of 5-ASA to decrease the multiplicity and size of colonic dyplasias as well as associated inflammation will be examined in Specific Aim 1. These data will be complemented by the use of MRI, colonoscopy and whole-body fluorescence imaging with biologically activated probes to monitor both the degree of inflammation (colon wall thickness) and the growth of polypoid and flat lesions over time. In Specific Aim 3, microarray-based analyses will be employed to compare and contrast the gene expression profile of inflamed nonneoplastic mucosa with that of polypoid and flat dysplasias as well as to identify those genes whose expression is altered in each tissue type following exposure to 5-ASA. Findings from these preclinical analyses are anticipated to enhance our understanding of the genetic basis of polypoid and flat colitis-associated dysplasias and facilitate the development of a chemopreventive regimen for ulcerative colitis patients at increased risk for colonic malignancies. PUBLIC HEALTH RELEVANCE: Because colonoscopies do not reliably detect early colon cancer in ulcerative colitis patients, there is a great need to develop a cancer preventive therapy for this high-risk population. Findings from the proposed mouse studies could lead to the use of 5-ASA for cancer prevention and significantly impact the establishment of future guidelines for the clinical management of patients with inflammatory bowel disease.