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Integrated analyses of cancers harboring STK11 vs. TSC1/2 vs. PTEN Loss

含有 STK11、TSC1/2 和 PTEN 缺失的癌症的综合分析

基本信息

批准号：
8915508
负责人：
DAVID J. KWIATKOWSKI
金额：
$ 47.51万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-24 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8915508
关键词：
Adult Affect Back CHEK1 gene CHES1 gene Cancer Family Cancer cell line Cell Line Clinical Critical Pathways Development Dose Essential Genes Family Frequencies Gene Targeting Genes Genetically Engineered Mouse Goals Growth Hamartoma Hereditary Disease Human Human Genetics Instruction Libraries Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of urinary bladder Methods Molecular Mus Names Neoplasms Oncogenes PTEN gene Pathogenesis Pathway interactions Pharmaceutical Preparations Pharmacotherapy Proteomics Recording of previous events STK11 gene Series Sirolimus Staging Syndrome TSC1/2 gene TSC2 gene Testing Therapeutic Therapy trial Tissues Translations Tumor Suppressor Genes cancer therapy comparative experience in vivo information gathering inhibitor/antagonist kinase inhibitor metabolomics mouse model mutant novel small hairpin RNA therapeutic target tumor

项目摘要

The four tumor suppressor genes LKBI (gene name STK11), TSCl, TSC2, and PTEN are known to be involved in a wide variety of human cancers, as well as causing human genetic disorders with a high frequency of specific neoplasms. Although drug therapies targeting the affected downstream pathways from the loss of these genes are at various stages of clinical development, including mTORCI inhibitors, clinical experience thus far suggests that in many instances such therapies have limited therapeutic potential in vivo. In this project, we propose a series of studies to examine the effects of loss of each of these four genes in human cancer and in genetically engineered mouse (GEM) models, to develop specific therapies. We will pursue the following specific aims in this proposal. First, we will perform a comparative analysis of human cancer cell lines with loss of TSCl vs. TSC2 vs. LKBI vs. PTEN to identify common and differential effects, and compensatory pathways through transcriptional, proteomic, and metabolomic profiles. Second, we will analyze GEM lung and bladder cancers with Tscl vs. Lkbl vs. Pten loss through similar studies. Third, we will perform a Global shRNA (synthetic lethal) screen to identify critical growth targets in GEM cancer primary cultures with Tscl vs. Lkbl vs. Pten loss. Finally, using information gathered from Aims 1 through 3, we will assess potential drug therapies in the GEM models involving these genes. Thus, we will use integrated approaches to identify critical pathways and therapeutic targets in tumors that have LKBI, TSC1/2, or PTEN loss.

四种肿瘤抑制基因LKBI（基因名称STK11）、TSCl、TSC2和PTEN是已知的