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MYC is a critical downstream effector in KRAS-driven pancreatic cancer

MYC 是 KRAS 驱动的胰腺癌中关键的下游效应子

基本信息

批准号：
8834866
负责人：
Brittany Allen-Petersen
金额：
$ 5.65万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
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：
2015-03-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8834866
关键词：
Biological Assay Cancer Etiology Cancer Patient Cancer cell line Cell Death Cell Survival Cell physiology Cells Cessation of life Clinical Data Desmoplastic Development Disease Progression Drug Targeting Ductal Epithelial Cells Goals Human Human Characteristics Immunofluorescence Immunologic In Vitro KRAS2 gene Lead Lesion Malignant Neoplasms Malignant neoplasm of pancreas Mediating Messenger RNA Metaplasia Modeling Modification Molecular Mus Mutate Mutation Normal tissue morphology Oncogene Proteins Oncogenic Pancreas Pancreatic Diseases Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Perfusion Phenotype Phosphorylation Phosphorylation Site Play Prevalence Proteins Proto-Oncogene Proteins c-myc Regulation Research Resistance Role Rosa Sampling Serine Signal Transduction Staging Stromal Neoplasm Survival Rate Testing Tissues United States base cancer cell cancer therapy cell growth cell transformation cell type chemotherapy human disease improved insight mouse model mutant new therapeutic target novel outcome forecast overexpression pancreatic cancer cells pancreatic neoplasm pancreatic tumorigenesis public health relevance therapeutic target therapy resistant tumor tumor initiation tumor progression tumorigenesis uncontrolled cell growth

项目摘要

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer related deaths in the United States. The 5-year survival rate for pancreatic cancer patients is only 6%, indicating a critical need for an improved understanding of pancreatic cancer development and identification of new therapeutic targets. MYC is a protein that strongly contributes to cancer progression in a wide variety of tissues and regulates several cellular functions that are corrupted during cancer development. Importantly, loss of MYC function can lead to cancer cell death and decreased tumor formation in mouse tumor models. Studies of MYC function have identified a modified form of MYC that has increased stability and activity. This form is found at high levels in several cancer cell types and leads to uncontrolled cell growth. Importantly, MYC is activated downstream of several factors known to be deregulated in pancreatic cancer. Specifically, the KRAS pathway, which is constitutively on in ~95% of all pancreatic ductal tumors, has been shown to contribute to MYC activation in other cell types. The role of MYC in pancreatic cancer, however, is poorly understood. The overall goal of this proposal is to determine if KRAS-mediated activation of MYC significantly contributes to pancreatic tumor progression. To achieve this goal, the proposed aims will utilize a novel mouse model of pancreatic cancer, patient tissue, and pancreatic cancer cells to investigate how MYC alters the initiation and progression of pancreatic cancer. Specifically, Aim 1 will determine if combining aberrant KRAS and MYC activity in a novel mouse model recapitulates the hallmarks of human pancreatic disease. Aim 2, will identify the stage at which MYC transitions to the more stable, active form in both human and mouse tumors. Finally, Aim 3 will determine if activation of MYC significantly contributes to the transformation of normal pancreatic cells to cancer cells downstream of KRAS signals. Pancreatic cancer remains highly resistant to cancer therapies. Alterations in the KRAS pathway occur in the majority of pancreatic cancer patients, however developing successful clinical drugs that target this protein has been unsuccessful. The proposed research will increase our understanding of the pathways that drive pancreatic cancer downstream of KRAS and potentially identify the proteins that control the activating modification of MYC as therapeutic targets in pancreatic cancer.