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（由应用提供）：结肠和直肠癌（结直肠癌）的癌症仍然是发病率和死亡率的主要原因。由于转移性结直肠癌对于手术不可切除的疾病患者仍然无法治愈，因此转移性结直肠癌模型的发展仍然是优先的。显示出侵袭和/或转移的小鼠肿瘤模型的可用性，并且与人类大肠癌具有显着相似性，将为识别导致恶性以及评估理论和预防策略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型的浸润性大肠癌模型，该模型在8-10个月大的年龄较高的侵入性结肠癌中，通过非侵入性PET和MRI成像可识别，并表达高水平的SRC和SRC活性。因此，SMAD3 +/-; rab25 - / - 小鼠代表了人类大肠癌的独特模型，并且可能是评估治疗的临床前工具。我们假设SMAD3 +/-; rab25 - / - 小鼠提供了与人类疾病高相关的结肠癌小鼠模型。本提案旨在以两个具体的目的开发该模型：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，这些肿瘤可以考虑增加侵入性特征。将肿瘤中的RNA测序结果与其他小鼠模型和人类有色癌症进行比较，以确定该模型的正确特征。普通生物标志物将通过免疫化学和定量PCR验证，以获得对侵入性癌症表型的更多了解。其次，我们将利用SMAD3 +/-; rab25- / - 小鼠中有色肿瘤的PET和MRI成像来评估结直肠癌的治疗策略。我们将评估SRC激酶家族抑制剂AZD-0530的有效性，以使用成像和病理标准调节SMAD3 +/-; RAB25 - / - 小鼠模型在SMAD3 +/-; RAB25 - / - 小鼠模型中的侵入性结直肠癌的进展。这些研究将支持结肠癌的SMAD3 +/-; RAB25 - / - 小鼠模型，这是评估侵入性结直肠癌临床治疗干预措施的关键场所。