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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：
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，我们将在一项新的干预性临床试验中检验以下假设：在一组高危家族性腺瘤性息肉病（FAP）和减毒FAP受试者中，同时抑制环加氧酶和EGFR将诱导十二指肠和结直肠腺瘤性息肉消退。在本试验中抑制的两种蛋白质类是在先前的资助周期中发现的，以介导突变型腺瘤性结肠息肉病（APC）基因的致癌作用。检查腺瘤消退和特异性标志物在临床试验中，这两种途径将不仅解决特定的临床需要，而且还将提供人类模型，用于确定这些途径在APC功能丧失后的致癌作用中是如何受到干扰的。这些相同的途径将在该计划的其他项目中在细胞培养，斑马鱼和小鼠模型中得到解决，从而形成一种统一的方法来确定APC功能丧失的下游影响。所获得的知识将有助于确定诊断、预防和治疗的新战略。治疗腺瘤性息肉和结肠癌。 FAP和减毒FAP受试者将被研究，因为多发性息肉表型，因为这些条件产生于遗传APC基因突变，相同的基因体细胞突变在大多数结肠腺瘤和癌症。安全有效的结肠息肉和结肠癌的化学预防对散发性和高风险形式的结直肠肿瘤都有很大的益处。十二指肠息肉和癌症是FAP和减毒FAP患者的特殊问题，因为目前的治疗远远不能令人满意。我们将在一项双盲、安慰剂对照试验中专门招募100名FAP和减毒FAP受试者，以检查舒林酸（一种通用考克斯抑制剂）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效应。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受试者的组合队列中抽取。补充本项目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将使用本项目中获得的适当样品。