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

前列腺癌(PCA)是中国最常见的男性癌症(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的有效一线疗法。 疾病。不幸的是，一旦前列腺癌复发，最终会发展为耐去势的前列腺癌 (CRPC)仍然是一种不治之症，需要更有效的治疗方法。目前，有限数量的 癌细胞系(LNCaP、PC3、DU-145等)可用于研究，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丢失)不是 在这样的单元格中代表。需要新的患者来源的癌症模型。然而，患者来源的异种移植 (PDX)模型在治疗侵袭性、高级别转移肿瘤和 有机培养物的效率只有20%。然而，我们的初步数据表明，有条件的 重新编程(CR)在建立长期培养方面几乎有100%的成功率 前列腺标本或CT引导下的活检。在本申请中，我们提出了以下具体目标 验证CR在人类CRPC中翻译使用的潜力。我们将首先从以下方面建立CR文化 30例慢性前列腺癌患者的活检标本，并将从遗传学和表型上描述这些培养的特征。第二, 我们将患者的药物反应与相应的肿瘤CR细胞及其衍生的CR- 衍生异种移植物(CDX)。最后，我们将在无偏见的高通量屏幕上使用CR培养来识别 与国家高级研究中心的克雷格·托马斯博士合作，为CRPC提供潜在的新疗法 翻译科学(NCATS)。来自屏幕的新的“命中”将通过体外细胞分析和 异种移植模型。

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.