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）是美国和全球癌症死亡的主要原因。在此应用中，我们将研究临时细胞白血病肿瘤抑制剂（PML），酪蛋白激酶2（CK2）和致癌K-RAS（ONC-K-RAS）对这种疾病的发病机理的贡献。此外，我们将在肺癌小鼠模型中测试CK2的药理抑制是否具有显着的抗肿瘤作用。 PML最初被确定为急性前临床白血病的PML-RAR1的成分，在多种肿瘤抑制功能中起着至关重要的作用，例如致癌基因诱导的复制衰老（OIS），凋亡和新血管生成。我们已经确定：1。PML经常在NSCLC和其他人类肿瘤中丢失，这是由于异常的泛素化而引起的，是由CK2（一种致癌蛋白激酶CK2）直接磷酸化引起的； 2。CK2抑制剂在异种移植模型中显示PML依赖性抗肿瘤特性； 3。PML损耗禁用OIS响应，导致由ONC-K-RAS启动的小鼠NSCLC模型中的肿瘤进展。这些观察结果表明：1。PML限制了不适当的细胞增殖，在体内充当真正的肿瘤抑制剂； 2。通过涉及异常PML泛素化和降解的机制，CK2激酶活性的上调有助于癌症的开始和进展。我们建议对控制OI的细胞网络有更好的了解将有助于开发新型的抗癌疗法。例如，鉴定控制PML肿瘤抑制活性，蛋白质稳定性和分解代谢的机制将为开发新的靶向药物提供框架。在这方面，预计CK2抑制剂将通过恢复癌细胞中的PML蛋白水平以及诱导和OIS反应发挥抗肿瘤作用。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，我们将在ONC-K-RAS引发的非小细胞肺癌模型中确定PML损失的功能意义。最后，我们将测试NSCLC小鼠模型中CK2特异性抑制剂的抗肿瘤特性。这些研究将阐明导致NSCLC肿瘤发生的机制，并为这种毁灭性疾病的新型治疗方法提供框架。公共卫生相关性：非小细胞肺癌（NSCLC）是与癌症相关死亡的主要原因。迫切需要新颖的治疗策略。通过这项建议，我们计划通过更好地了解反对癌症形成的分子网络来朝着这一目标迈进。我们将表征NSCLC中临床细胞抑制剂（PML）的肿瘤抑制特性。此外，我们还将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）来测试PML蛋白质恢复，这会导致体内抗肿瘤作用。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，忠实的肺癌NSCLC小鼠模型以及一组独特的新药物。这项工作将为制定一种新型策略来治疗这种毁灭性疾病的框架。