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：
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
项目类别：
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

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) 是男性中最常诊断出的癌症（2016 年新增病例 180,890 例）美国。雄激素剥夺疗法（ADT）是治疗局部晚期或转移性癌症的有效一线疗法。不幸的是，一旦前列腺癌复发，最终会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，目前需要更有效的治疗方法。癌细胞系（LnCAP、PC3、DU-145 等）可用于研究，并且许多基因突变存在于前列腺癌（例如 SPOP 突变、FOXA1 突变、TMPRSS2-ERG 融合、CHD1 缺失）不属于需要新的患者来源的癌症模型。然而，患者来源的异种移植模型。 (PDX) 模型在治疗侵袭性、高级别转移性肿瘤时的效率低于 2-5% 然而，我们的初步数据表明，类器官培养的效率仅为 20%。重编程 (CR) 对于通过手术或手术建立长期培养物的成功率接近 100% 前列腺标本或 CT 引导活检在此应用中，我们提出以下具体目标。验证 CR 在人类 CRPC 中转化应用的潜力我们将首先建立 CR 培养物。对 30 名 CRPC 患者进行活检，并对这些培养物进行遗传和表型表征。我们比较了患者对相应肿瘤 CR 细胞及其衍生 CR 的药物反应最后，我们将在无偏高通量筛选中使用 CR 培养物来识别。与国家高级中心的 Craig Thomas 博士合作治疗 CRPC 的新潜在疗法转化科学 (NCATS) 屏幕上的新“热门”将通过体外细胞测定和验证。异种移植模型。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Re: Kimmo Kettunen, Peter J. Boström, Tarja Lamminen, et al. Personalized Drug Sensitivity Screening for Bladder Cancer Using Conditionally Reprogrammed Patient-derived Cells. Eur Urol 2019;76:430-4: Can Patient-derived Cancer Models Change the Costliest

回复：Kimmo Kettunen、Peter J. Bostrom、Tarja Lamminen 等人。

DOI：
发表时间：
2020
期刊：
影响因子：
23.4
作者：
Liu; Xuefeng
通讯作者：
Xuefeng

Conditionally Reprogrammed Cells from Patient-Derived Xenograft to Model Neuroendocrine Prostate Cancer Development.

来自患者来源的异种移植物的条件性重编程细胞用于模拟神经内分泌前列腺癌的发展。

DOI：
发表时间：
2020
期刊：
影响因子：
6
作者：
Ci, Xinpei;Hao, Jun;Dong, Xin;Xue, Hui;Wu, Rebecca;Choi, Stephen Yiu Chuen;Haegert, Anne M;Collins, Colin C;Liu, Xuefeng;Lin, Dong;Wang, Yuzhuo
通讯作者：
Wang, Yuzhuo