Chemoprevention of Colitis-Associated Neoplasia by 5-ASA

描述(由申请人提供)： 尽管与普通人群相比，溃疡性结肠炎患者罹患结直肠癌的风险显著增加，但针对这一高危人群的化学预防干预措施的开发却鲜有人关注。此外，结肠镜检查不能可靠地发现溃疡性结肠炎患者的早期病变，特别是扁平不典型增生。来自该小组的初步数据证明，治疗人类结肠炎的一线药物5-氨基水杨酸(5-ASA)在诱导结肠炎之前给予AOM/DSS诱导的小鼠结肠炎相关发育不良的多样性，从而提供了拟议研究的理论基础。最有趣的是息肉样(体积缩小)和扁平(多样性减少)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对5-ASA暴露的反应可能不同，这些病变亚型可能通过独立的遗传途径发生。来自该小组的最新数据证实，在DSS诱导后给予5-ASA可以抑制结肠炎相关损害；这是一个临床相关的时间表。这项研究的总体目标是通过将新的成像技术与遗传图谱和生物信息学的最新进展相结合，对5-ASA对AOM/DSS诱导的结肠炎相关性结直肠癌的化学预防活性有新的认识。提出的实验假设是，5-ASA通过改变息肉和扁平病变的生长，通过不同的遗传途径有效地抑制结肠炎相关肿瘤的形成。对于最佳剂量的5-ASA减少结肠异型增生的多发性和大小以及相关炎症的能力将在特定的目标1中进行研究。这些数据将通过使用MRI、结肠镜和带有生物激活探针的全身荧光成像来补充，以监测炎症程度(结肠壁厚度)以及随着时间的推移息肉样病变和扁平病变的生长。在具体目标3中，基于基因芯片的分析将被用来比较和对比炎性非肿瘤性粘膜与息肉和扁平不典型增生的基因表达谱，并识别在暴露于5-ASA后在每种组织类型中表达发生变化的基因。这些临床前分析的结果有望增强我们对息肉和扁平结肠炎相关发育不良的遗传基础的理解，并促进针对结肠癌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发现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疗法。拟议中的小鼠研究结果可能导致5-ASA用于癌症预防，并对未来炎症性肠病患者临床治疗指南的建立产生重大影响。

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.