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

已知四种肿瘤抑制基因LKB 1（基因名称STK 11）、TSC 1、TSC 2和PTEN是肿瘤抑制基因。 与多种人类癌症有关，以及引起人类遗传性疾病， 特定肿瘤的频率。虽然针对受影响的下游途径的药物治疗， 这些基因的丧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，这种疗法在体内具有有限的治疗潜力。 在这个项目中，我们提出了一系列的研究，以检查这四个基因中的每一个的丢失对 人类癌症和基因工程小鼠（GEM）模型，以开发特定的治疗方法。我们将 在本建议中，力求实现以下具体目标。首先，我们将对人类进行比较分析。 TSC 1相对于TSC 2相对于LKBI相对于PTEN缺失的癌细胞系以鉴定共同和差异效应， 以及通过转录、蛋白质组学和代谢组学谱的补偿途径。二是 通过类似的研究分析GEM肺癌和膀胱癌的Tscl相对于Lkbl相对于Pten损失。三是 将进行一项全球性的shRNA（合成致死）筛选，以确定GEM癌症中的关键生长靶点 原代培养物中Tscl、LkBL和Pten丢失。最后，利用从目标1至3收集的信息， 我们将在涉及这些基因的GEM模型中评估潜在的药物治疗。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， TSC 1/2或PTEN缺失。

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.