Application of a humanized patient-derived xenograft mouse model to assess the preclinical efficacy of combined chemohyperthermia and chimeric TRAIL treatment in ovarian peritoneal carcinomatosis

摘要 卵巢癌（OvCA）在女性癌症死亡中排名第五，死亡人数超过其他任何癌症 妇科癌症每年，美国约有22，240名女性被诊断患有OvCA， 14,070人会死卵巢上皮癌占所有卵巢恶性肿瘤的约90%。典型的模式 OvCA的扩散和可能最早的转移类型是腹膜内扩散，卵巢腹膜转移， 癌病（OPC）。OPC是OvCA的常见终末进化，被认为是致死性疾病。在 在这项拨款申请中，我们假设一种多模式方法（生物化学的组合）， 试剂Fc-TRAIL（免疫球蛋白Fc结构域融合的肿瘤坏死因子相关凋亡诱导 配体）、化疗剂丝裂霉素C和轻度热疗）将有效地防止 通过促进凋亡性死亡来防止OPC复发。本项目的具体目标是：（1）调查 通过Fc-TRAIL，丝裂霉素C， 以及（2）建立人源化PDX（患者来源的异种移植物）小鼠 模型的OPC和检查临床前杀肿瘤疗效的多模式的方法。第一个目标，我们 将采用生物化学和分子技术来研究细胞凋亡的机制， OPC类器官的组合治疗。第二个目的是建立PDX肿瘤模型， 人源化三重转基因NSGTM-SGM3小鼠（非肥胖糖尿病/严重联合免疫缺陷 表达人白细胞介素-3、粒细胞-巨噬细胞集落刺激因子的NOD/SCID γ小鼠， 和干细胞因子）并评估对组合治疗的反应。我们认为，自从NSG ™- SGM3小鼠是经证实的用于人肿瘤移植以及人肿瘤细胞株建立的宿主。 造血干细胞移植后的免疫，我们预期人源化PDX小鼠模型将 保留了原始肿瘤和重建的人类免疫系统的大部分特征。我们认为 本研究的成功结果将支持人源化PDX小鼠的有用应用 模型，以评估这种新型的基于嵌合TRAIL的疗法与HIPEC疗法联合治疗患有 OPC。

ABSTRACT Ovarian cancer (OvCA) ranks fifth in cancer deaths among women, accounting for more deaths than any other gynecologic cancer. Each year, ~22,240 women in the United States will be diagnosed with OvCA, and ~14,070 will die. Ovarian epithelial cancer represents ~90% of all ovarian malignant tumors. The typical pattern of spread and probably the earliest kind of metastasis of OvCA is intraperitoneal spread, ovarian peritoneal carcinomatosis (OPC). OPC is a frequent terminal evolution of OvCA and is considered a lethal condition. In this grant application, we hypothesize that a multimodal approach (a combination of the biochemical agent Fc-TRAIL (immunoglobulin Fc domain fused tumor necrosis factor-related apoptosis-inducing ligand), the chemotherapeutic agent mitomycin C, and mild hyperthermia) will effectively prevent recurrence of OPC by promoting apoptotic death. The specific aims of this project are to: (1) investigate the mechanism of synergistic induction of cytotoxicity by the combinatorial treatment of Fc-TRAIL, mitomycin C, and hyperthermia in OPC organoids; and (2) establish a humanized PDX (patient-derived xenograft) mouse model of OPC and examine the preclinical tumoricidal efficacy of the multimodal approach. In the first aim, we will employ biochemical and molecular techniques to investigate the mechanism of apoptotic death during the combinatorial treatment in OPC organoids. In the second aim, we will establish PDX tumor models with humanized triple transgenic NSGTM-SGM3 mice (nonobese diabetic/severe combined immunodeficiency NOD/SCID gamma mice expressing human interleukin-3, granulocyte-macrophage colony-stimulating factor, and stem cell factor) and assess the response to the combinatorial treatment. We believe that since NSG™- SGM3 mice are a proven host for engraftment of human tumors as well as the establishment of human immunity following hematopoietic stem cell transplantation, we expect that humanized PDX mouse models will retain most of the characteristics of the original tumors and reconstituted human immune system. We believe that the successful outcome of this study will support the useful application of the humanized PDX mouse model to assess this novel chimeric TRAIL-based therapy in combination with HIPEC therapy to patients with OPC.