Conditionally Reprogrammed Cell Model for Castration-Resistant Prostate Cancer (CRPC)

去势抵抗性前列腺癌 (CRPC) 的条件重编程细胞模型

基本信息

批准号：
10223223
负责人：
Xuefeng Liu
金额：
$ 48.22万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10223223
关键词：
Biopsy CHD1 gene Cancer Center Cancer Model Cancer Patient Cancer cell line Cell model Cells Cellular Assay Collaborations Cultured Cells DNA Sequence Alteration DU145 Data Development Disease Environment Epithelial European Goals Human In Vitro LNCaP Malignant neoplasm of prostate Metastatic Prostate Cancer Modeling Mutation National Cancer Institute Nature Neoplasm Metastasis Operative Surgical Procedures Organoids PC3 cell line Paper Pathway interactions Patients Pharmaceutical Preparations Phenotype Prostate Protocols documentation Publishing Research Research Project Grants Specimen TMPRSS2 gene Technology Therapeutic Agents Translational Research United States Urology Work Xenograft Model Xenograft procedure androgen deprivation therapy anticancer research cancer diagnosis castration resistant prostate cancer cell stroma docetaxel drug response prediction effective therapy exome sequencing high throughput screening men novel drug class patient derived xenograft model patient response prostate cancer cell response success transcriptome translational model translational study tumor tumor xenograft

项目摘要

Prostate cancer (PCa) is the most frequently diagnosed cancer (180,890 new cases in 2016) in men in the USA. Androgen deprivation therapy (ADT) is an effective first line therapy for locally advanced or metastatic disease. Unfortunately, once PCa recurs, the eventual development of castration-resistant prostate cancer (CRPC) remains an incurable disease and more effective therapies are needed. Currently, a limited number of cancer cell lines (LnCAP, PC3, DU-145, etc.) are available for research and many genetic mutations present in prostate cancer (e.g., SPOP mutation, FOXA1 mutation, TMPRSS2-ERG fusion, CHD1 loss) are not represented in such cells. New patient-derived cancer models are needed. However, patient-derived xenograft (PDX) models are successful at less than 2-5% efficiency with aggressive, high-grade metastatic tumors and organoid cultures only have an efficiency of 20%. However, our preliminary data demonstrate that conditional reprogramming (CR) has nearly a 100% success rate for establishing long-term cultures from either surgical prostate specimens or CT-guided biopsies. In this application, we propose the following specific aims to validate the potential of CR for translational use in human CRPC. We will first establish CR cultures from biopsies of 30 patients with CRPC and will characterize these culture genetically and phenotypically. Second, we compare the patients' drug response to those of corresponding tumor CR cells and their derivative CR- derived xenografts (CDXs). Lastly, we will use CR cultures in an unbiased high-throughput screen to identify new potential therapies for CRPC in collaboration with Dr. Craig Thomas at National Center for Advanced Translational Sciences (NCATS). New “hits” from the screen will be validated by both in vitro cell assays and xenograft models.

前列腺癌（PCA）是男性最常见的癌症（2016年180,890例新病例）美国。雄激素剥夺疗法（ADT）是用于局部晚期或转移性的有效第一线治疗疾病。不幸的是，一旦PCA复发，castration抗性前列腺癌的事件发展（CRPC）仍然是一种无法治愈的疾病，需要更有效的疗法。目前，数量有限癌细胞系（LNCAP，PC3，DU-145等）可用于研究，并且存在许多基因突变前列腺癌（例如，Spop突变，FOXA1突变，TMPRSS2-erg融合，CHD1损失）不是在此类细胞中表示。需要新的患者来源的癌症模型。但是，患者衍生的异种移植物（PDX）模型的效率低于2-5％的成功，具有侵略性的高级转移性肿瘤和器官培养物的效率仅为20％。但是，我们的初步数据证明了条件重新编程（CR）几乎具有100％的成功率，可以从任何一种手术中建立长期培养前列腺标本或CT引导的活检。在此应用中，我们提出以下具体目的验证CR在人CRPC中翻译使用的潜力。我们将首先建立CR培养 30例CRPC患者的活检将以典型和表型为特征。第二，我们将患者的药物反应与相应肿瘤CR细胞及其衍生物CR-的药物反应进行比较派生的异种移植物（CDXS）。最后，我们将在公正的高通量屏幕中使用CR培养物来识别 CRPC的新潜在疗法与国家高级中心的Craig Thomas博士合作翻译科学（NCAT）。屏幕上的新“命中”将通过体外细胞分析和异种移植模型。