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

已知的四个肿瘤抑制基因LKBI(基因名为STK11)、TSC1、TSC2和PTEN是 与多种人类癌症有关，并导致人类遗传性疾病 特定肿瘤的发生频率。尽管针对受影响的下游通路的药物疗法 这些基因的丢失处于临床发展的不同阶段，包括mTORCI抑制剂、临床 到目前为止的经验表明，在许多情况下，这种疗法在体内的治疗潜力有限。 在这个项目中，我们提出了一系列研究，以检验这四个基因中的每一个的丢失在 在人类癌症和基因工程小鼠(GEM)模型中，开发特定的治疗方法。我们会 在这项提案中追求以下具体目标。首先，我们将对人类进行比较分析 TSC1、TSC2、LKBI、PTEN缺失的癌细胞系，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。第二，我们将 通过类似的研究，用Tscl、Lkbl和Pten Lost来分析宝石、肺癌和膀胱癌。第三，我们 将进行全球shRNA(合成致死)筛查以确定宝石癌的关键生长靶点 Tscl与Lkbl与Pten Lost的原代培养。最后，使用从目标1到目标3收集的信息， 我们将评估GEM模型中涉及这些基因的潜在药物疗法。因此，我们将使用 在有LKBI的肿瘤中识别关键途径和治疗靶点的综合方法， TSC1/2，或PTEN丢失。

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.