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

肺癌 PML 肿瘤抑制因子的表征和药物靶向

• 批准号: 8193127
• 负责人: PIER Paolo SCAGLIONI
• 金额: $ 31.6万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8193127
• 关键词: Ablation; Acute Promyelocytic Leukemia; Address; Adenocarcinoma; Apoptosis; Cancer Etiology; Cancer Model; Catabolism; Cell Aging; Cell Proliferation; Cessation of life; Development; Disease; Drug Delivery Systems; Event; Genes; Goals; Health; Human; Lesion; Light; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Modeling; Molecular; Mus; Non-Small-Cell Lung Carcinoma; Oncogenes; Oncogenic; Pathogenesis; Pharmaceutical Preparations; Phenotype; Phosphorylation; Phosphotransferases; Play; Property; Protein Deficiency; Protein Kinase; Proteins; Role; Signal Transduction; Specimen; System; Testing; Tumor Burden; Tumor Suppressor Proteins; Ubiquitin; Ubiquitination; Up-Regulation; Work; Xenograft Model; adenoma; cancer cell; cancer initiation; cancer therapy; casein kinase II; in vivo; inhibitor/antagonist; mouse model; mutant; novel; novel strategies; novel therapeutic intervention; novel therapeutics; research study; response; restoration; tumor; tumor progression; tumorigenesis

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.

描述（由申请人提供）：非小细胞肺癌（NSCLC）是美国和全世界癌症死亡的主要原因。在此应用中，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 (CK2) 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CK2的药理学抑制是否具有显着的抗肿瘤作用。 PML 最初被鉴定为急性早幼粒细胞白血病 PML-RAR1 的组成部分，在多种肿瘤抑制功能中发挥着关键作用，例如诱导癌基因诱导的复制衰老 (OIS)、细胞凋亡和新血管生成。我们已经确定： 1. 由于 CK2（一种致癌蛋白激酶）直接磷酸化引发的异常泛素化，PML 在 NSCLC 和其他人类肿瘤中经常丢失； 2. CK2抑制剂在异种移植模型中表现出PML依赖性抗肿瘤特性； 3. 在由 onc-K-Ras 引发的小鼠 NSCLC 模型中，Pml 丢失使 OIS 反应失效，导致肿瘤进展。这些观察结果表明： 1. PML 限制不适当的细胞增殖，在体内充当真正的肿瘤抑制因子； 2. CK2激酶活性上调通过涉及异常PML泛素化和降解的机制促进癌症的发生和进展。我们建议更好地了解控制 OIS 的细胞网络将有助于开发新型抗癌疗法。例如，控制 PML 肿瘤抑制活性、蛋白质稳定性和分解代谢的机制的识别将为开发新型靶向药物提供框架。在这方面，CK2抑制剂有望通过恢复癌细胞内的PML蛋白水平并诱导OIS反应来发挥抗肿瘤作用。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 onc-K-Ras 引发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 CK2 特异性抑制剂的体内抗肿瘤特性。这些研究将揭示导致非小细胞肺癌肿瘤发生的机制，并将为开发这种破坏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。通过这项提议，我们计划通过更好地了解反对癌症形成的分子网络来实现这一目标。我们将描述早幼粒细胞肿瘤抑制因子 (PML) 在 NSCLC 中的肿瘤抑制特性。此外，我们将测试通过抑制酪蛋白激酶 2（一种有助于 NSCLC 肿瘤发生的致癌蛋白激酶）恢复 PML 蛋白是否会在体内产生抗肿瘤作用。我们将按照综合策略进行这些实验，该策略将利用细胞系统、肺癌非小细胞肺癌的忠实小鼠模型和一套独特的新药。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。