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Novel Mouse Models to define Genetic Drivers of Aggressive Prostate Cancer

定义侵袭性前列腺癌遗传驱动因素的新型小鼠模型

基本信息

批准号：
9461668
负责人：
Leigh Ellis
金额：
$ 17.13万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-15 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9461668
关键词：
Address Adenocarcinoma Androgen Receptor Automobile Driving Biological Markers Biology Cancer Patient Candidate Disease Gene Clinical Collection Controlled Environment Development Disease Disease Progression Epigenetic Process Epithelial Cells Epithelium Event Evolution Gene Expression Genetic Genetic Screening Genetically Engineered Mouse Goals Human Indolent Insertional Mutagenesis Intraepithelial Neoplasia Investigation Knowledge Lead Ligands LoxP-flanked allele MYC gene Malignant Neoplasms Malignant neoplasm of prostate Mediating Metastatic Prostate Cancer Metastatic to Modeling Molecular Mus Mutagenesis Mutation Neoplasm Metastasis Neoplasms Organ Pathway interactions Patients Phenotype Primary Neoplasm Prostate Prostatic Intraepithelial Neoplasias Research Resources Retinoblastoma Protein Retrotransposon Sampling Serum Sleeping Beauty Stratification TP53 gene Testing Time Transgenic Mice Transgenic Model Transgenic Organisms Transposase Validation anticancer research base bone cancer initiation disease phenotype gene discovery human disease loss of function mutation mortality mouse model novel novel marker novel therapeutics overexpression potential biomarker prostate cancer model public health relevance therapeutic target tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): A fundamental gap in knowledge in prostate cancer (PCa) is how to distinguish indolent from aggressive disease. Further, genetic events that switch an indolent PCa to an aggressive phenotype are not well understood. Our proposed investigations will utilize two state-of-the-art genetically engineered mouse models (GEMMs) of PCa generated by the PI to address these gaps in knowledge. Expression of the Myc oncogene exclusive to mouse prostate epithelium results in indolent organ confined PCa. We have combined the Myc transgenic mouse model with additional models to establish novel GEMMs of PCa to perform a gene candidate and gene discovery approach to delineate genetic drivers of aggressive PCa progression. Specifically, aim 1 will determine if the retinoblastoma protein (Rb) is a suppressor of PCa metastasis. Specific aim 2 will utilize a sleeping beauty mutagenesis screen to identify novel candidate genetic drivers of PCa metastasis. Ultimately, these novel and state-of-the-art mouse models allow for prostate specific molecular events to be investigated. Our principle objective is to characterize our GEMMs to discover genetic switches which drive aggressive PCa. Overall, our proposed studies will significantly impact PCa research and how patients are clinically assessed to determine stratification of indolent from aggressive disease. In addition, through completing these studies, we will continue to achieve our longer term goals which are to identify and validate new therapeutic pathways/targets that may ultimately be used to treat patients with advanced PCa, and serum available biomarkers of PCa that identify aggressive PCa phenotypes.

描述(由申请人提供)：前列腺癌(PCA)知识的一个基本空白是如何区分惰性和侵袭性疾病。此外，将惰性前列腺癌转变为攻击性表型的遗传事件还没有被很好地理解。我们建议的研究将利用PI产生的两个最先进的PCa基因工程小鼠模型(GEMM)来解决这些知识差距。Myc癌基因在小鼠前列腺上皮细胞中的表达导致惰性器官受限的前列腺癌。我们将Myc转基因小鼠模型与其他模型相结合，建立了新的前列腺癌GEMM，以执行基因候选和基因发现的方法来描述侵袭性前列腺癌进展的遗传驱动因素。具体地说，Aim 1将确定视网膜母细胞瘤蛋白(Rb)是否是PCa转移的抑制因子。特定目的2将利用睡美人突变筛选来确定新的前列腺癌转移候选遗传驱动因素。最终，这些新颖和最先进的小鼠模型允许研究前列腺特异性分子事件。我们的主要目标是描述我们的GEMM，以发现驱动侵袭性PCA的遗传开关。总体而言，我们建议的研究将显著影响PCA研究以及如何对患者进行临床评估，以确定惰性疾病与侵袭性疾病的分层。此外，通过完成这些研究，我们将继续实现我们的长期目标，即确定和验证最终可能用于治疗晚期PCa患者的新的治疗途径/目标，以及识别侵袭性PCa表型的可用的PCa生物标志物。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Evidence that EZH2 Deregulation is an Actionable Therapeutic Target for Prevention of Prostate Cancer.

DOI：
10.1158/1940-6207.capr-20-0186
发表时间：
2020-12
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
0
作者：
Burkhart DL;Morel KL;Wadosky KM;Labbé DP;Galbo PM;Dalimov Z;Xu B;Loda M;Ellis L
通讯作者：
Ellis L