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.

项目概要 Rb 肿瘤抑制因子在相对较小的肺组织中突变失活腺癌，但在大多数情况下 Rb 通路通常可能失活。这个场景为针对 Rb 上游负调节因子（即细胞周期蛋白依赖性）的治疗奠定了基础激酶，重新激活 Rb 的肿瘤抑制功能。目前多项临床试验正在进行中在某些癌症类型中已经发现了此类疗法的功效和显着的临床益处。然而，即使在这些情况下，治疗持久性也不确定，目前尚不清楚 Rb 是否再激活对于包括肺腺癌在内的许多其他肿瘤类型都有效。添加到此不确定性是令人惊讶的认识，即 Rb 或一般 Rb 途径在致癌 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：目标 1 侧重于确定基因工程小鼠肺中 Rb 突变的功能后果腺癌模型和人类肺癌标本。相比之下，该提案的目标 2 侧重于使用我们实验室最近开发的遗传工具对 Rb 再激活疗法进行建模，该工具允许肿瘤发展过程中 Rb 的条件失活，以及 Rb 的诱导和精确再激活一旦癌症确诊。在我们的初步发现的推动下，我们在目标 1 中的总体假设是： Rb 的缺失通过消除两个不同的障碍来加速肺腺癌的进展限制腺瘤-癌转变的序列，然后限制转移能力的发生。在目标 2 中，我们的初步见解提出了这样的假设：Rb 恢复在已建立的肺中起主要作用腺癌是重建抑制性染色质结构，从而导致晚期肿瘤的逆转促转移基因表达程序的等级和抑制。我们期望我们的研究将揭示驱动 Rb 途径突变选择的机制，并确定 Rb 通路恢复对肺腺癌的治疗效果。此外，我们的研究将强调 Rb 途径在疾病相关背景下利用的特定生化程序，这些程序可能是治疗刺激以重现这种关键肿瘤抑制因子的自然功能。这些见解可能广泛适用于含有 Rb 途径突变的许多肿瘤类型。