Role of the RB Tumor Suppression in Liver Tumorigenesis

RB 肿瘤抑制在肝脏肿瘤发生中的作用

基本信息

批准号：
9663130
负责人：
Erik Knudsen
金额：
$ 44.08万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9663130
关键词：
Address Adhesions Automobile Driving Bypass CDK4 gene CDKN2A gene Cancer Etiology Carcinogens Cell Cycle Cessation of life Clinical Clinical Trials Complex Development Diagnosis Disease Disease Progression Etiology Event Exposure to Failure Financial compensation Funding Genes Genetic Genetic Models Health Hepatic Hepatocarcinogenesis Human Hyperplasia Incidence Intervention Lesion Liver Liver neoplasms Malignant Neoplasms Malignant neoplasm of liver Mediating Metabolic Diseases Modeling Molecular Analysis Monitor Mus Mutagens Normal tissue morphology Oncogenes Pathway interactions Phosphorylation Play Primary carcinoma of the liver cells Process Protein Deregulation Role S Phase Seeds Specimen Stem cells Stress Testing Therapeutic Therapeutic Intervention Transcription Process Transcriptional Activation Transcriptional Regulation Tumor Suppression Tumor Suppressor Genes Tumor Suppressor Proteins Virus Diseases Work advanced disease base carcinogenicity cdc Genes genome integrity genotoxicity inhibitor/antagonist insight mouse model novel novel therapeutic intervention outcome forecast preclinical study prevent public health relevance response retinoblastoma tumor suppressor targeted treatment tumor tumor initiation tumor progression

项目摘要

DESCRIPTION (provided by applicant): Hepatocellular Carcinoma is a major health concern. Currently, this disease is the 3rd leading cause of cancer deaths worldwide with over 500,000 new diagnoses each year. This high incidence of hepatocellular carcinoma development is attributed to environmental insults ranging from exposure to hepatocarcinogens, viral infections, to metabolic disorders. One of the key genetic lesions found in liver cancer is inactivation of the retinoblastoma tumor suppressor (RB) pathway. This pathway is disrupted in most liver tumors via a number of discrete mechanisms including loss of RB gene or deregulation of protein phosphorylation (e.g., p16ink4a loss). Over the last funding cycle we extensively interrogated how RB loss contributes to tumor development. In mouse models, we found that in the absence of carcinogenic stress RB loss is insufficient for tumor development. This is due to extensive compensation of the RB-deficient state and led us to explore unique functions of RB that are not subject to compensatory processes. These analyses demonstrated a novel function of RB in maintaining transcriptional control and cell cycle exit in the presence of specific carcinogenic stresses. Consonantly, RB-deficiency was associated with significantly increased tumor development under such conditions. These combined findings provide the basis for fully understanding how RB-status impinges on transcriptional processes under stress conditions and the specific consequence related to genome integrity driving tumor development (Aim 1). Interestingly, in the course of these studies we found that RB loss is associated with rapid proliferation and progression to advanced tumor grade in mouse models. Molecular analysis of mouse and human HCC tumors revealed that RB plays a complex role on cell cycle and other processes (e.g., adhesion and EMT) that are relevant for disease progression and associate with poor prognosis. The poor survival of HCC is due, in part, to failure to effectively treat advanced disease. Given the key role of RB in tumor etiology/progression, we investigated the ability to activate the RB-pathway as a therapeutic strategy. The findings from these studies indicated that it is possible to therapeutically reinstate the RB-pathway using specific CDK4/6 inhibitors, which are being tested in clinical trials. These combined findings provide the basis fo determining how RB modulates disease progression and how to systematically target the RB-pathway therapeutically in the treatment of HCC (Aim 2).

描述（由申请人提供）：肝细胞癌是一个主要的健康问题，目前，这种疾病是全球癌症死亡的第三大原因，每年有超过 500,000 例新诊断的肝细胞癌的高发病率归因于环境损害。接触肝癌物质、病毒感染、代谢紊乱是肝癌中发现的关键遗传病变之一。视网膜母细胞瘤肿瘤抑制 (RB) 通路在大多数肝脏肿瘤中通过许多离散机制被破坏，包括 RB 基因的丢失或蛋白质磷酸化的失调（例如，p16ink4a 丢失）。在小鼠模型中，我们发现在没有致癌应激的情况下，RB 损失不足以促进肿瘤的发展，这是由于 RB 缺乏状态的广泛补偿。引导我们探索不受代偿过程影响的 RB 独特功能。这些分析证明了 RB 在特定致癌应激存在下维持转录控制和细胞周期退出的新功能。这些发现为充分了解应激条件下 RB 状态如何影响转录过程以及与驱动肿瘤发展的基因组完整性相关的特定后果奠定了基础（目标 1）。这些研究发现，RB 丢失与小鼠模型中的快速增殖和进展为晚期肿瘤相关。对小鼠和人类 HCC 肿瘤的分子分析表明，RB 在细胞周期和其他过程（例如粘附和 EMT）中发挥着复杂的作用。鉴于 RB 在肿瘤病因/进展中的关键作用，HCC 的生存率较差，部分原因是 RB 在肿瘤病因/进展中的关键作用。 RB 通路作为一种治疗策略这些研究的结果表明，可以使用特定的 CDK4/6 抑制剂来治疗恢复 RB 通路，这些抑制剂正在临床试验中进行测试，这些综合结果为确定 RB 的作用提供了基础。调节疾病进展以及如何在 HCC 治疗中系统地靶向 RB 通路（目标 2）。