Discovering New Targets for Chemoprevention in Familial Adenomatous Polyposis

发现家族性腺瘤性息肉病化学预防的新靶点

• 批准号: 8619924
• 负责人: Eduardo Vilar Sanchez
• 金额: $ 8万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8619924
• 关键词: APC gene; Adenomatous Polyposis Coli; Anti-Inflammatory Agents; Anti-inflammatory; Bioinformatics; Biological Markers; Carcinoma; Carpet; Cause of Death; Chemoprevention; Chemopreventive Agent; Clinical; Clinical Research; Colectomy; Colon; Colonic Polyps; Colorectal; Colorectal Adenoma; Computer Simulation; Data; Data Set; Development; Diagnosis; Disease; Drug Targeting; Duodenal Adenoma; Duodenum; Duodenum Cancer; Gastrointestinal Neoplasms; Gastrointestinal tract structure; Gene Expression; Gene Expression Profile; General Population; Genetic; Genomics; Goals; Hereditary Disease; Individual; Intervention; Knowledge; Lead; Lesion; Life; Location; Mission; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Mucous Membrane; Mutation; Natural History; Non-Steroidal Anti-Inflammatory Agents; Operative Surgical Procedures; Outcome; PTGS2 gene; Pathway interactions; Patients; Pharmaceutical Preparations; Polypoid Lesion; Polyps; Premalignant; Prevention strategy; Preventive; Public Health; Rectum; Research; Secondary to; Small Intestines; Systems Biology; Techniques; Technology; Testing; Time; Work; adenoma; base; carcinogenesis; drug development; exome; gastrointestinal; inhibitor/antagonist; innovation; lifetime risk; malignant small intestine tumor; mortality; next generation sequencing; polyposis; prevent; prophylactic; public health relevance; research study; response; tool; transcriptomics

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.

描述（由申请人提供）：已经表明，涉及非甾体类抗炎药（NSAIDS）和COX-2抑制剂的化学预防策略减少了家族性腺瘤性息肉病（FAP）患者的息肉负担。但是，尚未观察到对十二指肠出现的病变的相同作用。这一事实表明，理解十二指肠息肉与FAP患者的结肠菌的分子差异存在基本差距。这种知识对于在该疾病中发展新的预防剂至关重要。长期目标是为FAP患者开发新的化学预防疗法。此特定应用中的目的是 生成初步数据，以确定可以通过充分表征这些病变的外显子组和转录组来确定对Duodenal腺瘤的药物干预的新靶标。中心假设是，与结直肠腺瘤相比，十二指肠腺瘤具有不同的分子改变谱，尽管两种类型的病变都是在共同的遗传基础上（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鉴定针对这些病变的新化学预防药物至关重要。强调该提案的理由是基于不同临床研究的观察结果，即用NSAIDS进行化学预防，可有效地减少息肉的数量并延迟结肠和直肠的腺瘤进展，几乎对双生性病变具有可忽略的作用。此外，十二指肠息肉的自然历史是腺瘤到 - 卡道瘤序列的缓慢且延长的过程。该假设将通过追求两个具体的目的来检验：1）比较十二指肠腺瘤的基因组和基因表达谱与患者匹配的结直肠腺瘤的患者和正常粘膜的基因组和基因表达谱以及FAP患者的两个位置的正常粘膜； 2）使用系统生物学工具鉴定用于FAP患者中的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名FAP患者的十二指肠和大肠息肉病变的外显子和转录组。在第二个目标下，将开发生物信息学工具，以将两个下一代测序工具与使用Systems Biology Tools的现有公共可用数据集集成到现有的公共可用数据集中。这些生物信息学工具将被利用，以发现新的目标和分量，以作为化学预防剂开发。这种方法具有创新性，因为将下一代测序技术和系统生物学工具首次结合在一起，以研究遗传疾病中的抗胃肠道疾病的前胃肠道病变并鉴定新的靶向化学预防剂。拟议的研究很重要，因为有望导致FAP预防的新药理策略的发展。这最终将导致降低十二指肠癌继发的死亡率，以及在十二指肠腺瘤病患者中进行的预防性手术的发病率。