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：
8719034
负责人：
DAVID J. KWIATKOWSKI
金额：
$ 46.33万
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
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8719034
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 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.

已知四种肿瘤抑制基因LKBI(基因名称STK11)、TSC1、TSC2和PTEN是涉及多种人类癌症，并导致人类遗传疾病的风险很高特定肿瘤的频率。尽管针对受影响的下游途径的药物疗法这些基因的丢失处于临床开发的各个阶段，包括 mTORCI 抑制剂、临床迄今为止的经验表明，在许多情况下，此类疗法的体内治疗潜力有限。在这个项目中，我们提出了一系列研究来检验这四个基因中每一个基因缺失的影响。人类癌症和基因工程小鼠（GEM）模型，以开发特定的疗法。我们将在本提案中追求以下具体目标。首先，我们对人类进行比较分析具有 TSC1 缺失的癌细胞系与 TSC2 对比 LKBI 对比 PTEN，以确定共同和差异效应，以及通过转录、蛋白质组和代谢组谱的补偿途径。其次，我们将通过类似的研究分析 GEM 肺癌和膀胱癌的 Tscl、Lkbl 和 Pten 丢失情况。第三，我们将进行全局 shRNA（合成致死）筛选，以确定 GEM 癌症的关键生长目标具有 Tscl 与 Lkbl 与 Pten 损失的原代培养物。最后，利用从目标 1 到目标 3 收集的信息，我们将评估涉及这些基因的 GEM 模型中潜在的药物疗法。因此，我们将使用识别具有 LKBI 的肿瘤中的关键途径和治疗靶点的综合方法， TSC1/2 或 PTEN 丢失。