Genetic events leading to APC-dependent colon cancer in high-risk families:COX

高危家族中导致 APC 依赖性结肠癌的遗传事件：COX

基本信息

批准号：
7786712
负责人：
RANDALL Walter BURT
金额：
$ 131.5万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-12 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7786712
关键词：
APC gene Aberrant crypt foci Address Adenocarcinoma Adenomatous Polyposis Coli Adenomatous Polyps Aftercare Attenuated Biopsy Specimen Caliber Cancer Etiology Cancer Patient Cardiotoxicity Cell Culture Techniques Cell physiology Cessation of life Chemoprevention Chemopreventive Agent Clinical Clinical Trials Colectomy Colon Colon Carcinoma Colonic Adenoma Colonic Polyps Colorectal Colorectal Adenoma Colorectal Neoplasms Colorectal Polyp Combination Medication Complement Complex Cyclins Cyclooxygenase Inhibitors Diagnosis Dose Duodenal Adenocarcinoma Duodenal Adenoma Duodenum Duodenum Cancer Enrollment Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib Event FDA approved Family Funding Gene Mutation Genes Genetic Genus Cola Germ-Line Mutation Growth Factor Human Inflammation Mediators Inherited Intestinal Mucosa Intestinal Neoplasms Intestinal Polyps Intestines KRAS2 gene Knowledge Large Intestine Loss of Heterozygosity MAP2K1 gene MEKs Malignant Neoplasms Mediating Microscopic Minority Modeling Molecular Molecular Genetics Morbidity - disease rate Mucous Membrane Mutate Mutation Neoplastic Cell Transformation Normal tissue morphology Nuclear Nuclear Translocation Oncogenic Pathway interactions Patients Phase Phenotype Phosphorylation Placebo Control Placebos Polyps Pongidae Prevention Preventive Prostaglandin-Endoperoxide Synthase Prostaglandins Prostaglandins I Proteins Proto-Oncogene Proteins c-akt Psychological reinforcement Publishing Randomized Receptor Activation Receptor Signaling Retinoids Risk Sampling Series Signal Pathway Signal Transduction Small Intestines Staging Sulindac Sulindac Sulfone Sum Testing Thromboxanes Tissues Up-Regulation WNT Signaling Pathway Zebrafish adenoma carcinogenesis celecoxib cohort combinatorial cyclooxygenase 2 double-blind placebo controlled trial duodenectomy high risk lifetime risk loss of function migration mortality mouse model mutant neoplasm registry novel novel strategies polyposis prevent programs rectal transcription factor tumorigenesis

项目摘要

In Project 1 we will test the hypothesis in a novel interventional clinical trial that concurrent inhibition of cyclo-oxygenases and EGFR will induce duodenal and colorectal adenomatous polyp regression in a cohort of high-risk, familial adenomatous polyposis (FAP) and attenuated FAP subjects. The two protein classes inhibited in this trial were found in the previous funding cycle to mediate the oncogenic effects of mutant adenomatous polyposis coli (APC) gene. Examining adenoma regression and specific markers of these two pathways in a clinical trial will not only address specific clinical needs, but will also provide the human model for defining how these pathways are perturbed in carcinogenesis following loss of APC function. These same pathways will be addressed in the other projects of this Program in cell culture, zebrafish and mouse models, thereby forming a unified approach to determining downstream effects of APC function loss. The knowledge gained will serve to identify novel strategies for diagnosis, prevention and treatment of adenomatous polyps and colon cancer. FAP and attenuated FAP subjects will be studied both because of the multiple polyp phenotype, and because these conditions arise from inherited APC gene mutations, the same gene somatically mutated in the large majority of colon adenomas and cancers. Safe and effective chemoprevention for colon polyps and cancer would be of substantial benefit for both sporadic and high risk forms of colorectal neoplasia. Duodenal polyps and cancer are a particular problem for FAP and attenuated FAP patients, as present treatments are far from satisfactory. We will specifically enroll 100 FAP and attenuated FAP subjects in a double blind, placebo controlled trial to examine the combinatorial effect of sulindac (a general COX inhibitor) and erlotinib (an EGFR inhibitor) to induce regression of duodenal and colorectal adenomatous polyps. We will draw from a combined cohort of approximately 300 local FAP and attenuated FAP subjects in our high-risk familial colon cancer registry. Secondary endpoints that complement the studies of other projects of this Program include: the change in aberrant crypt foci before and after treatment; and, changes in expression of WNT, EGFR and KRAS cellular signaling pathways in both adenomatous polyp and normal tissue biopsy samples. Finally, appropriate samples obtained in this project will be utilized by Projects 2-4.

在项目 1 中，我们将在一项新颖的介入性临床试验中测试这一假设，即同时抑制环氧合酶和 EGFR 将在一组高危家族性腺瘤性息肉病 (FAP) 和减毒 FAP 受试者中诱导十二指肠和结直肠腺瘤性息肉消退。本试验中抑制的两类蛋白质是在之前的资助周期中发现的，可介导突变型腺瘤性结肠息肉病 (APC) 基因的致癌作用。检查腺瘤消退和特定标志物临床试验中的这两条途径不仅可以满足特定的临床需求，而且还将提供人体模型来定义这些途径在 APC 功能丧失后在致癌过程中如何受到干扰。这些相同的途径将在本计划的细胞培养、斑马鱼和小鼠模型的其他项目中得到解决，从而形成确定 APC 功能丧失的下游影响的统一方法。所获得的知识将有助于确定诊断、预防和治疗的新策略。治疗腺瘤性息肉和结肠癌。将研究 FAP 和减毒 FAP 受试者，因为其具有多种息肉表型，而且这些病症是由遗传性 APC 基因突变引起的，同一基因在大多数结肠腺瘤和癌症中发生体细胞突变。对结肠息肉和癌症进行安全有效的化学预防将对散发性和高风险形式的结直肠肿瘤产生巨大益处。十二指肠息肉和癌症对于 FAP 和减毒 FAP 患者来说是一个特殊的问题，因为目前的治疗方法远不能令人满意。我们将专门招募 100 名 FAP 和减毒 FAP 受试者进行双盲、安慰剂对照试验，以检查舒林酸（一种普通 COX 抑制剂）和厄洛替尼（一种 EGFR 抑制剂）诱导十二指肠和结直肠腺瘤性息肉消退的组合作用。我们将从我们的高风险家族性结肠癌登记处的约 300 名当地 FAP 和减毒 FAP 受试者组成的联合队列中进行抽取。补充该计划其他项目研究的次要终点包括：治疗前后异常隐窝病灶的变化；腺瘤性息肉和正常组织活检样本中 WNT、EGFR 和 KRAS 细胞信号通路表达的变化。最后，项目 2-4 将利用本项目中获得的适当样本。