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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：
8234098
负责人：
RANDALL Walter BURT
金额：
$ 35.6万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8234098
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 Adenocarcinoma 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 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 TCF7L2 gene 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，我们将在一项新的干预性临床试验中检验这一假设，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)和减弱型FAP受试者中诱导十二指肠和结直肠腺瘤性息肉消退。在这项试验中被抑制的两种蛋白质类别是在前一个资金周期中被发现的，以介导突变的腺瘤性息肉病结肠(APC)基因的致癌效应。腺瘤消退与肿瘤特异性标志物的检测临床试验中的这两条途径不仅将满足特定的临床需求，还将提供人体模型，以确定这些途径在APC功能丧失后如何在癌症发生中受到干扰。这些相同的途径将在本计划的其他细胞培养、斑马鱼和小鼠模型项目中解决，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新的诊断、预防和治疗腺瘤性息肉和结肠癌。 FAP和弱化FAP受试者将被研究，因为这些疾病都是由于多发性息肉表型，而且由于这些疾病是由遗传的APC基因突变引起的，相同的基因在绝大多数结肠腺瘤和癌症中发生了体细胞突变。对结肠息肉和癌症进行安全有效的化学预防对零星和高危形式的大肠肿瘤都有很大好处。十二指肠息肉和癌症是FAP和弱化FAP患者的一个特别问题，因为目前的治疗方法远远不能令人满意。我们将专门招募100名FAP和减重FAP受试者参加一项双盲、安慰剂对照试验，以检验舒林酸(一种通用的COX抑制剂)和厄洛替尼(一种EGFR抑制剂)在诱导十二指肠和结直肠腺瘤性息肉消退方面的联合作用。我们将从我们的高危家族性结肠癌登记中大约300名局部FAP和减弱型FAP受试者的联合队列中进行研究。补充本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；以及腺瘤性息肉和正常组织活检标本中WNT、EGFR和KRAS细胞信号通路表达的变化。最后，项目2-4将利用在该项目中获得的适当样本。