Characterization and drug targeting of the PML tumor suppressor in lung cancer

描述（由申请人提供）：非小细胞肺癌（NSCLC）是美国和全球癌症死亡的主要原因。在本申请中，我们将研究早幼粒细胞白血病肿瘤抑制因子（PML）、酪蛋白激酶2（CK 2）和致癌K-RAS（onc-K-RAS）对该疾病发病机制的贡献。此外，我们将在肺癌小鼠模型中测试CK 2的药理学抑制是否具有显著的抗肿瘤作用。PML最初被鉴定为急性早幼粒细胞白血病的PML-RAR 1的组分，在多种肿瘤抑制功能中起关键作用，例如诱导癌基因诱导的复制性衰老（OIS）、细胞凋亡和新血管生成。我们已经确定：1。PML在NSCLC和其他人类肿瘤中经常丢失，这是由于由CK 2（一种致癌蛋白激酶）直接磷酸化触发的异常泛素化; 2. CK 2抑制剂在异种移植模型中显示PML依赖性抗肿瘤特性; 3. Pml损失使OIS应答失效，导致由onc-K-Ras引发的小鼠NSCLC模型中的肿瘤进展。这些观察意味着：1。PML抑制不适当的细胞增殖，在体内充当真正的肿瘤抑制剂; 2. CK 2激酶活性的上调通过涉及异常PML泛素化和降解的机制促进癌症的发生和发展。我们建议，更好地了解控制OIS的细胞网络将有助于开发新的抗癌疗法。例如，控制PML肿瘤抑制活性、蛋白质稳定性和催化剂的机制的鉴定将为开发新的靶向药物提供框架。在这方面，预期CK 2抑制剂通过恢复癌细胞内的PML蛋白水平并诱导OIS应答来发挥抗肿瘤作用。我们将通过确定介导PML肿瘤抑制功能的机制来解决这些假设。此外，我们将确定在onc-K-Ras启动的非小细胞肺癌模型中PML丢失的功能意义。最后，我们将在NSCLC小鼠模型中测试CK 2特异性抑制剂的体内抗肿瘤特性。这些研究将阐明导致NSCLC肿瘤发生的机制，并为开发这种毁灭性疾病的新治疗方法提供框架。公共卫生相关性：非小细胞肺癌（NSCLC）是癌症相关死亡的主要原因。迫切需要新的治疗策略。有了这个提议，我们计划通过更好地了解对抗癌症形成的分子网络来实现这一目标。我们将描述NSCLC中早幼粒细胞肿瘤抑制因子（PML）的肿瘤抑制特性。此外，我们将检测通过抑制酪蛋白激酶2（一种致癌蛋白激酶，有助于NSCLC肿瘤发生）恢复PML蛋白是否会导致体内抗肿瘤作用。我们将按照一种综合策略进行这些实验，该策略将利用细胞系统、肺癌NSCLC的忠实小鼠模型和一组独特的新药。这项工作将为开发治疗这种毁灭性疾病的新策略提供框架。

DESCRIPTION (provided by applicant): Non-small cell lung cancer (NSCLC) is a leading cause of cancer death in the US and worldwide. In this application, we will study the contribution of the promyelocytic leukemia tumor suppressor (PML), casein kinase 2 (CK2), and oncogenic K-RAS (onc-K-RAS) to the pathogenesis of this disease. In addition, we will test in mouse models of lung cancer whether pharmacological inhibition of CK2 has a significant anti-tumor effect. PML, initially identified as a component of the PML-RAR1 of acute promyelocytic leukemia, plays a critical role in multiple tumor suppressive functions such as induction of oncogene induced replicative senescence (OIS), apoptosis, and neoangiogenesis. We have determined that: 1. PML is frequently lost in NSCLC and other human tumors due to aberrant ubiquitination triggered by direct phosphorylation by CK2, an oncogenic protein kinase; 2. CK2 inhibitors display PML dependent anti-tumor properties in xenograft models; 3. Pml loss disables the OIS response leading to tumor progression in a mouse NSCLC model initiated by onc-K-Ras. These observations imply that: 1. PML constrains inappropriate cell proliferation, acting as a bona fide tumor suppressor in vivo; 2. upregulation of CK2 kinase activity contributes to cancer initiation and progression through a mechanism that involves aberrant PML ubiquitination and degradation. We propose that a better understanding of the cellular networks controlling OIS will be instrumental for the development of novel anti-cancer therapies. For example, the identification of the mechanisms controlling PML tumor suppressive activity, protein stability and catabolism will provide the framework for the development of novel targeted drugs. In this regards, CK2 inhibitors are expected to exert an anti-tumor effect by restoring PML protein levels within cancer cells and inducing and OIS response. We will address these hypotheses by identifying the mechanisms that mediate PML tumor suppressive function. In addition, we will determine the functional significance of PML loss in a model of non-small cell lung cancer initiated by onc-K-Ras. Finally, we will test the anti-tumor properties of specific inhibitors of CK2 in vivo in mouse models of NSCLC. These studies will shed light on the mechanisms leading to NSCLC tumorigenesis and will provide the framework for the development of novel therapeutic approaches for this devastating disease. PUBLIC HEALTH RELEVANCE: Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related death. Novel therapeutic strategies are urgently needed. With this proposal, we are planning to move toward this goal by gaining a better understanding of the molecular networks that oppose cancer formation. We will characterize the tumor suppressive properties of the promyelocytic tumor suppressor (PML) in NSCLC. In addition, we will test whether PML protein restoration through inhibition of casein kinase 2, an oncogenic protein kinase that contributes to NSCLC tumorigenesis, leads to an antitumor effect in vivo. We will perform these experiments following an integrated strategy that will utilize cellular systems, a faithful mouse model of lung cancer NSCLC and a unique set of novel drugs. This work will provide the framework for the development of a novel strategy for the treatment of this devastating disease.