Mouse model of invasive colon cancer

侵袭性结肠癌小鼠模型

基本信息

批准号：
9248192
负责人：
JAMES Richard GOLDENRING
金额：
$ 15.75万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9248192
关键词：
Accounting Age-Months Apoptosis Biological Markers Cancer Etiology Cancer Model Cell physiology Cessation of life Characteristics Colon Carcinoma Colonic Neoplasms Colorectal Cancer Colorectal Neoplasms Detection Development Disease Evaluation Genetic Transcription Health Human Image Immunochemistry Inflammation Lead Magnetic Resonance Imaging Malignant Neoplasms Messenger RNA Methodology MicroRNAs Modeling Molecular Genetics Molecular Profiling Morbidity - disease rate Mucous Membrane Mus Neoplasm Metastasis Patients Pattern Phenotype Physiological Processes Physiology Positron-Emission Tomography Prevention strategy RNA Rectum Subgroup Therapeutic Therapeutic Intervention Transcript Treatment Efficacy Tumor Markers Up-Regulation base human cancer mouse model human disease imaging modality in vivo inhibitor/antagonist kinase inhibitor metastatic colorectal miRNA expression profiling model development molecular imaging mortality mouse model novel pre-clinical pre-clinical research src-Family Kinases tool transcriptome sequencing tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Cancers of the colon and rectum (colorectal cancer) remain a major cause of morbidity and mortality. Since metastatic colorectal cancer remains largely incurable for patients with surgically non-resectable disease, the development of models of metastatic colorectal cancer remains a priority. The availability of a mouse tumor model that demonstrates invasion and/or metastasis and has prominent similarity to human colorectal cancer would provide a powerful tool for identifying the genetic and molecular alterations that lead to malignancy as well as for assessment of therapeutic and preventive strategies. We have recently developed a novel model of invasive colorectal cancer in Smad3+/-;Rab25-/- mice, which develop invasive colon cancers by 8-10 months of age that are identifiable by non-invasive PET and MRI imaging and express high levels of Src and Src activity. The Smad3+/-;Rab25-/- mouse therefore represents a unique model for colorectal cancer in humans and may be of considerable value as a pre-clinical tool for evaluating therapeutic efficacy. We have hypothesized that the Smad3+/-;Rab25-/- mouse provides a robust mouse model of colon cancer with high correlation to human disease. The present proposal seeks to develop this model in two specific aims: First, we will evaluate the differences in RNA expression patterns in Smad3+/-;Rab25-/- mouse colorectal tumors that could account for increased invasive characteristics. RNA sequencing results in tumors will be compared with both other mouse models and human colorectal cancers to determine the correlative characteristics of this model. Common biomarkers will be validated by immunochemistry and quantitative PCR to obtain a greater understanding of the invasive cancer phenotype. Second, we will utilize PET and MRI imaging of colorectal tumors in the Smad3+/-;Rab25- /- mouse to evaluate therapeutic strategies in colorectal cancer. We will assess the efficacy of AZD-0530, a Src kinase family inhibitor, in modulating the progression of invasive colorectal cancers in the Smad3+/-;Rab25-/- mouse model using both imaging and pathological criteria. These studies will facilitate the development of the Smad3+/- ;Rab25-/- mouse model of colon cancer as a critical venue for the evaluation of pre- clinical therapeutic interventions in invasive colorectal cancer.

描述（由申请人提供）：结肠癌和直肠癌（结直肠癌）仍然是发病和死亡的主要原因，因为对于患有不可手术切除疾病的患者来说，转移性结直肠癌在很大程度上仍然无法治愈，因此转移性结直肠癌模型的开发。证明侵袭和/或转移且与人类结直肠癌具有显着相似性的小鼠肿瘤模型的可用性将为识别导致的遗传和分子改变提供强大的工具。我们最近在 Smad3+/-;Rab25-/- 小鼠中开发了一种新的侵袭性结肠直肠癌模型，这些小鼠在 8-10 个月大时会发展为可识别的侵袭性结肠癌。通过非侵入性 PET 和 MRI 成像，Smad3+/-;Rab25-/- 小鼠表达高水平的 Src 和 Src 活性，因此代表了人类结直肠癌的独特模型。作为评估治疗效果的临床前工具具有相当大的价值。我们一直致力于提供与人类疾病高度相关的稳健的结肠癌小鼠模型。该模型有两个具体目标：首先，我们将评估 Smad3+/-;Rab25-/- 小鼠结直肠肿瘤中 RNA 表达模式的差异，这可以解释肿瘤中侵袭性特征增加的原因，并将与其他小鼠进行比较。模型和人类结直肠癌，以确定该模型的相关特征，将通过免疫化学和定量 PCR 进行验证，以更好地了解 Smad3+ 中的侵袭性癌症表型。 /-;Rab25- /- 小鼠评估结直肠癌的治疗策略我们将评估 AZD-0530（一种 Src 激酶家族抑制剂）在调节结直肠癌进展方面的功效。使用成像和病理标准在 Smad3+/-;Rab25-/- 小鼠模型中评估侵袭性结直肠癌这些研究将促进 Smad3+/-;Rab25-/- 结肠癌小鼠模型的开发，作为评估的关键场所。侵袭性结直肠癌的临床前治疗干预。