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

• 批准号: 10478023
• 负责人: Xuefeng Liu
• 金额: $ 47.11万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10478023
• 关键词: Biopsy; CHD1 gene; Cancer Center; Cancer Model; Cancer Patient; Cancer cell line; Cell model; Cells; Cellular Assay; Collaborations; 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; National Center for Advancing Translational Sciences; 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; enzalutamide; exome sequencing; high throughput screening; men; novel drug class; patient derived xenograft model; patient response; prostate cancer cell; response; success; transcriptome; translational applications; translational model; translational study; tumor; tumor xenograft

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）是美国男性中最常诊断的癌症（2016年新发病例180，890例）。 USA.雄激素剥夺治疗（ADT）是局部晚期或转移性前列腺癌的有效一线治疗方法， 疾病不幸的是，一旦前列腺癌复发，最终发展为去势抵抗性前列腺癌， CRPC仍然是一种无法治愈的疾病，需要更有效的治疗方法。目前，数量有限的 癌细胞系（LnCAP、PC 3、DU-145等）可供研究，许多基因突变存在于 前列腺癌（例如，SPOP突变、FOXA 1突变、TMPRSS 2-ERG融合、CHD 1缺失）， 在这些细胞中。需要新的患者来源的癌症模型。然而，患者来源的异种移植物 (PDX)模型对于侵袭性、高级别转移性肿瘤的成功率低于2-5%， 类器官培养物只有20%的效率。然而，我们的初步数据表明， 重编程（CR）在建立长期培养物方面的成功率接近100%， 前列腺标本或CT引导活检。在本申请中，我们提出以下具体目标， 验证CR在人CRPC中转化使用的潜力。我们将首先建立CR文化， 30例CRPC患者的活检，并将这些文化的遗传和表型特征。第二、 我们将患者的药物反应与相应的肿瘤CR细胞及其衍生物CR的反应进行了比较， 衍生异种移植物（CDX）。最后，我们将使用CR文化在一个公正的高通量筛选，以确定 与国家高级研究中心的克雷格托马斯博士合作， 翻译科学（NCATS）。来自筛选的新的“命中”将通过体外细胞测定和 异种移植模型。