Deconstructing the multi-faceted roles of Rb in tumor progression

解构 Rb 在肿瘤进展中的多方面作用

基本信息

批准号：
9755390
负责人：
David Feldser
金额：
$ 35.72万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2018-08-03 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9755390
关键词：
ATAC-seq Affect Alleles Antitumor Response Biochemical Biological Biological Models Carcinoma Cell Cycle Cells ChIP-seq Chromatin Chromatin Structure Clinical Clinical Trials Competence Coupled Cyclin-Dependent Kinase Inhibitor Cyclin-Dependent Kinases Data Development Disease Disease Progression Embryo Enterobacteria phage P1 Cre recombinase Epithelial Cells Etiology G1/S Transition Gene Expression Genes Genetic Genetically Engineered Mouse Genomic approach Goals Histologic Human Inhalation Knowledge Laboratories Lead Longevity Lung Lung Adenocarcinoma MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of lung Mediating Modeling Molecular Mus Mutation Oncogenic Pathway interactions Play Positioning Attribute Recording of previous events Repression Research Retinoblastoma Retinoblastoma Genes Role Signal Transduction Specimen System TP53 gene Therapeutic Tissues Treatment Efficacy Tumor Initiators Tumor Suppression Tumor Suppressor Proteins Uncertainty Viral Vector Work adenoma base cancer therapy cancer type derepression efficacy testing experience gene function histological specimens improved in vivo in vivo imaging innovation insight interest malignant breast neoplasm mouse model neoplastic cell programs response restoration retinoblastoma tumor suppressor success targeted treatment tool transcription factor transcriptome sequencing treatment strategy tumor tumor progression

项目摘要

PROJECT SUMMARY The Rb tumor suppressor is mutationally inactivated in relatively small fraction of lung adenocarcinomas, but the Rb pathway in general is likely inactivated in the majority of cases. This scenario sets the stage for therapies targeting the upstream negative regulators of Rb, namely cyclin dependent kinases, to reactivate Rb's tumor suppressive functions. Currently, multiple clinical trials are underway to test the efficacy of such therapies and significant clinical benefits have been discovered in certain cancer types. However, even in these cases the therapeutic durability is uncertain and it is currently unknown whether Rb reactivation will be effective in many other tumor types including lung adenocarcinoma. Adding to this uncertainty is the surprising realization that the role of Rb, or the Rb pathway in general, in oncogenic Kras- driven lung adenocarcinomas is unclear. Therefore, our project has two major goals: Aim 1 focuses on determining the functional consequences of Rb mutations in both genetically engineered mouse lung adenocarcinoma models and in human lung cancer specimens. In contrast, Aim 2 of this proposal focuses on modeling Rb reactivation therapy using a genetic tool recently developed in our laboratory that allows both, the conditional inactivation of Rb during tumor development, and the inducible and accurate reactivation of Rb once cancers are established. Fueled by our preliminary findings, our overarching hypothesis in Aim 1 is that loss of Rb accelerates lung adenocarcinoma progression by removing two distinct barriers that work in sequence to limit the adenoma-carcinoma transition, and then the onset of metastatic competency. In Aim 2, our initial insights suggest the hypothesis that the major role of Rb restoration in established lung adenocarcinomas is to reestablish repressive chromatin structures that lead to the reversal of advanced tumor grades and repression of pro-metastatic gene expression programs. We expect that our study will uncover the mechanisms that drive selection of Rb pathway mutations, and establish the therapeutic efficacy of Rb pathway restoration in lung adenocarcinoma. Further, our study will highlight specific biochemical programs utilized by the Rb pathway in disease relevant contexts that could be therapeutically stimulated to recapitulate the natural functions of this critical tumor suppressor. These insights may be broadly applicable to the many tumor types that harbor Rb pathway mutations.

项目摘要 RB肿瘤抑制剂在相对较小的肺部突变灭活腺癌，但在大多数情况下，RB途径通常会灭活。这种情况设定针对RB上游负调节剂的治疗阶段，即依赖细胞周期蛋白激酶，重新激活RB的肿瘤抑制功能。目前，正在进行多次临床试验进行测试在某些癌症类型中已经发现了这种疗法和重大临床益处的功效。但是，即使在这些情况下，治疗耐用性也不确定，目前尚不清楚RB是否重新激活将在许多其他肿瘤类型中有效，包括肺腺癌。加上这个不确定性是令人惊讶的认识到，RB或RB途径在致癌性Kras中的作用驱动的肺腺癌尚不清楚。因此，我们的项目有两个主要目标：AIM 1专注于确定两个基因工程小鼠肺中RB突变的功能后果腺癌模型和人类肺癌标本。相比之下，本提案的目标2着重于使用最近在我们的实验室中开发的遗传工具对RB重新激活疗法进行建模肿瘤发育过程中RB的条件失活以及RB的诱导和准确重新激活建立癌症后。在我们的初步发现的推动下，我们在AIM 1中的总体假设是 RB的损失通过消除两个不同的障碍来加速肺腺癌的进展序列以限制腺瘤 - c- c肾上腺瘤过渡，然后限制转移能力的发作。在AIM 2中，我们最初的见解表明，RB恢复在已建立的肺中的主要作用腺癌是重新建立导致晚期肿瘤逆转的抑制性染色质结构促源基因表达程序的等级和抑制。我们预计我们的研究将发现推动RB途径突变选择的机制，并确定肺腺癌中RB途径恢复的治疗功效。此外，我们的研究将突出显示RB途径在疾病相关环境中使用的特定特定的生化程序在治疗上刺激以概括这种严重的肿瘤抑制剂的自然功能。这些见解可以广泛适用于许多具有RB途径突变的肿瘤类型。