乳腺癌PDX模型的建立和抗体药物的筛选.pdfVIP

乳腺癌PDX 模型的建立和抗体药物的筛选 摘 要 乳腺癌是目前全世界女性最常见的恶性肿瘤之一，也是导致女性癌症死亡的重要因 素。但是乳腺癌的病因尚未清楚，到目前为止并未找到乳腺癌确切的致癌原因。乳腺癌 包含有多种不同的亚型，他们在遗传，病理和临床表现上都不相同，这也为乳腺癌的临 床诊断和治愈增加难度。病人来源的肿瘤组织异种移植（Patient-Derived Tumor Xenograft ， PDX ）模型依赖于将肿瘤标本直接移植到重症免疫缺陷的动物中，从而构建临床前模型， 是预测体内肿瘤治疗的常用方法。PDX 模型通过将新鲜的肿瘤样本直接移植到免疫缺 陷型小鼠体内，既保留了肿瘤的异质性，也为个性化治疗提供了可能性。 本研究收集 49 例新鲜乳腺癌临床样本，并分别通过皮下注射到重症免疫缺陷型小 鼠（NCG ）体内。截至目前为止，49 例样品中，20 例乳腺癌样品（40.8% ）在小鼠体内 成功生长。通过对临床因素做相关性分析，三阴性乳腺癌样品 PDX 模型的成瘤率显著 高于非三阴性乳腺癌样品（P=0.0140 ），CK5/6 阳性表达的样品PDX 模型成瘤率也显著 高于CK5/6 阴性的样品（P=0.0144 ）。 利用本研究成功建立的PDX 小鼠模型，分离出乳腺癌单细胞，通过体外侵袭实验， 筛选到具有抑制肿瘤细胞侵袭功能的抗ROR2 的抗体，药效动力学实验表明，该抗体的 半衰期是在50 小时。最后，通过PDX 小鼠体内抗肿瘤实验研究，我们发现该抗体能有 效抑制乳腺癌PDX 模型的肿瘤增长。 关键词：乳腺癌，PDX ，抗体筛选 I Establishment of Breast Cancer PDX Model and Screening of Antibody Drugs Abstract Breast cancer is currently one of the most common malignant tumors worldwide and is a major cause of cancer-related deaths in women. However, the pathogenesis of breast cancer remains to be elucidated. There are many subtypes in breast cancer with different genetic, pathological and clinical manifestations, which makes it more difficult for clinical diagnosis and treatment of breast cancer. Patient-derived tumor xenograft (PDX) model is established by directly transplanting human tumor specimens into animals with severe immunodeficiency, which is a commonly used tool for evaluating the efficacy of different tumor treatment in vivo. The advantage of the PDX model is that it retains tumor heterogeneity and provides the opportunity for developing personalized treatment. In this study, a total of 49 fresh breast cancer clinical samples were collected from hospitals, and were injected subcutaneously into severe immunodeficiency mice (NCG) to establish breas