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

• 批准号: 10227061
• 负责人: David Feldser
• 金额: $ 36.83万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/10227061
• 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; KRAS oncogenesis; Knowledge; Laboratories; Lead; Longevity; Lung; Lung Adenocarcinoma; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Modeling; Molecular; Mus; Mutation; 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 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 pathway; retinoblastoma tumor suppressor; success; targeted treatment; tool; transcription factor; transcriptome sequencing; treatment strategy; tumor; tumor progression

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肿瘤抑制基因在相对小的肺组织中突变失活 在大多数情况下，Rb通路通常是失活的。这种情况 为靶向Rb的上游负调节因子，即细胞周期蛋白依赖性 激酶，以重新激活Rb的肿瘤抑制功能。目前，多项临床试验正在进行中， 已经在某些癌症类型中发现了这种疗法的功效和显著的临床益处。 然而，即使在这些情况下，治疗的持久性是不确定的，目前还不清楚是否Rb 再活化在包括肺腺癌在内的许多其它肿瘤类型中是有效的。添加到这一点 不确定性是令人惊讶的认识，Rb的作用，或Rb途径一般，在致癌Kras- 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Rb突变在基因工程小鼠肺中的功能后果， 腺癌模型和人肺癌标本中的细胞毒性。相比之下，本提案的目标2侧重于 使用我们实验室最近开发的遗传工具模拟Rb激活疗法， Rb在肿瘤发展过程中的条件性失活，以及Rb的可诱导和准确的再激活 一旦癌症形成。在我们的初步发现的推动下，我们在目标1中的首要假设是， Rb的缺失通过消除两个不同的屏障加速肺腺癌的进展， 序列，以限制腺瘤-癌转变，然后转移能力的开始。在目标2中， 我们的初步见解提出了这样的假设，即Rb恢复在已建立的肺组织中的主要作用， 腺癌是重建抑制性染色质结构，导致晚期肿瘤逆转， 促转移基因表达程序的分级和抑制。 我们希望我们的研究将揭示驱动Rb途径突变选择的机制， 建立Rb通路修复对肺腺癌的治疗效果。此外，我们的研究将 强调Rb通路在疾病相关背景下使用的特定生物化学程序， 治疗刺激，以概括这种关键的肿瘤抑制因子的天然功能。这些见解 可广泛应用于具有Rb通路突变的许多肿瘤类型。