Discovering New Targets for Chemoprevention in Familial Adenomatous Polyposis

描述（由申请方提供）：研究表明，涉及非甾体抗炎药（NSAID）和考克斯-2抑制剂的化学预防策略可减少家族性腺瘤性息肉病（FAP）患者结肠直肠中的息肉负担。然而，在十二指肠病变中未观察到相同的效果。这一事实表明，在理解FAP患者的十二指肠和结直肠息肉之间的分子差异方面存在根本性的差距。这些知识对于开发新的化学预防剂是必不可少的。长期目标是为FAP患者开发新的化学预防疗法。本申请的目的是 通过充分表征这些病变的外显子组和转录组，产生初步数据以确定适合FAP患者十二指肠腺瘤药物干预的新靶点。中心假设是，十二指肠腺瘤，与结直肠腺瘤相比，有不同的分子改变的配置文件，虽然这两种类型的病变出现在一个共同的遗传基础（即APC改变）。因此，对FAP中十二指肠息肉的外显子组和转录组的全面注释对于识别针对这些病变的新的化学预防药物至关重要。强调这一建议的基本原理是基于不同临床研究中的观察结果，即NSAID的化学预防在减少结肠和直肠息肉数量和延迟腺瘤进展方面被证明是有效的，对十二指肠病变的影响几乎可以忽略不计。此外，十二指肠息肉的自然病程是值得注意的，因为腺瘤到癌的顺序是缓慢和延长的过程。该假设将通过追求两个特定目标进行检验：1）比较FAP患者中十二指肠腺瘤与患者匹配的结直肠腺瘤和正常周围粘膜的基因组和基因表达谱; 2）通过使用系统生物学工具鉴定靶向FAP患者十二指肠腺瘤的分子途径和候选化合物。在第一个目标下，下一代测序技术将用于表征10例FAP患者的十二指肠和结直肠息肉样病变的外显子组和转录组。在第二个目标下，将开发生物信息学工具，利用系统生物学工具将两种下一代测序工具生成的数据整合到现有的公开数据集。这些生物信息学工具将被用来发现新的靶标和化合物，以开发为化学预防剂。该方法是创新的，因为它首次结合了下一代测序技术和系统生物学工具的使用，以研究遗传性疾病中的癌前胃肠道病变，并确定新的靶向化学预防剂。这项研究具有重要意义，因为它有望导致开发新的预防FAP的药理学策略。这将最终导致降低继发于十二指肠癌的死亡率，以及十二指肠腺瘤病患者预防性手术的发病率。

DESCRIPTION (provided by applicant): It has been shown that chemopreventive strategies involving nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors reduce the polyp burden in the colorectum of patients with Familial Adenomatous Polyposis (FAP). However, the same effect has not been observed on lesions arising in the duodenum. This fact indicates that there is a fundamental gap in understanding the molecular differences between polyps arising in the duodenum and the colorectum of patients with FAP. This knowledge is essential to develop new chemo- preventive agents in this disease. The long-term goal is to develop new chemopreventive therapies for patients with FAP. The objective in this particular application is to generate preliminary data to identify new targets that are amenable to drug intervention in duodenal adenomas of patients with FAP by fully characterizing the exome and transcriptome of these lesions. The central hypothesis is that duodenal adenomas, compared with colorectal adenomas, have distinct molecular alteration profiles, although both types of lesions arise on a common genetic basis (i.e. APC alterations). Therefore, a comprehensive annotation of the exome and transcriptome of duodenal polyps in FAP will be critical to identify new chemoprevention drugs targeting these lesions. The rationale that underlines this proposal is based on the observation in different clinical studies that chemoprevention with NSAIDs, proven effective in reducing the number of polyps and delaying adenoma progression in the colon and rectum, has had almost negligible effect on duodenal lesions. In addition, the natural history of duodenal polyps is notable for a slow and prolonged course of the adenoma-to-carcinoma sequence. This hypothesis will be tested by pursuing two specific aims: 1) To compare the genomic and gene expression profiles of duodenal adenomas with those of patient-matched colorectal adenomas and normal surrounding mucosa from both locations in patients with FAP; 2) To identify molecular pathways and candidate compounds for targeting duodenal adenomas in FAP patients by using systems biology tools. Under the first aim, next generation sequencing techniques will be used to characterize the exome and transcriptome of duodenal and colorectal polypoid lesions in 10 patients with FAP. Under the second aim, bioinformatics tools will be developed to integrate the data generated with both next-generation sequencing tools into existing publicly available data sets using systems biology tools. These bioinformatic tools will be exploited to discover new targets and com- pounds to be developed as chemopreventive agents. The approach is innovative because is combining the use of next-generation sequencing technologies and systems biology tools for the first time to study premalignant gastrointestinal lesions in a genetic disease and to identify new targeted chemopreventive agents. The proposed research is significant because is expected to lead to the development of new pharmacologic strategies for prevention in FAP. This will ultimately lead to the reduction of the mortality secondary to duodenal carcinomas, and morbidity of prophylactic surgeries performed in patients with duodenal adenomatosis.