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（由适用提供）：肝细胞癌是一个主要的健康问题。目前，这种疾病是全世界癌症死亡的第三主要原因，每年有超过500,000个新诊断。肝细胞癌发育的这种高部分归因于环境感染，从暴露到肝癌，病毒感染到代谢性疾病。肝癌中发现的关键遗传病变之一是失活视网膜细胞瘤肿瘤抑制（RB）途径。该途径在大多数肝肿瘤中都通过多种离散机制破坏了，包括失去RB基因或对蛋白质磷酸化的失调（例如，P16INK4A损失）。在上一个融资周期中，我们广泛询问了RB损失如何有助于肿瘤的发展。在小鼠模型中，我们发现在没有致癌应力的情况下，RB损失不足以用于肿瘤发育。这是由于对RB缺陷状态的广泛补偿，使我们探索了不受补偿过程的RB的独特功能。这些分析表明，在存在特定的致癌应力的情况下，RB在维持转录控制和细胞周期退出方面具有新的功能。同时，在这种情况下，RB缺陷与肿瘤发育显着增加有关。这些结合发现为完全理解RB状态如何影响转录过程中的转录过程以及与基因组完整性驱动肿瘤发展有关的具体后果提供了基础（AIM 1）。有趣的是，在这些研究过程中，我们发现RB损失与小鼠模型中的快速增殖和向晚期肿瘤等级的发展有关。小鼠和人类HCC肿瘤的分子分析表明，RB在细胞周期和其他与疾病进展相关的过程中起着复杂的作用（例如粘合剂和EMT），并且与预后不良有关。 HCC生存不良的部分原因是未能有效治疗晚期疾病。鉴于RB在肿瘤病因/进展中的关键作用，我们研究了激活RB-Pathway作为治疗策略的能力。这些研究的发现表明，可以使用特定的CDK4/6抑制剂在治疗中恢复RB-Pathway，这些抑制剂正在临床试验中进行测试。这些结合发现提供了基础，以确定RB如何调节疾病进展以及如何系统地靶向RB-Pathway在治疗HCC时（AIM 2）。