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

应用人源化异种移植小鼠模型评估联合化疗和嵌合 TRAIL 治疗卵巢腹膜癌的临床前疗效

基本信息

批准号：
10058826
负责人：
YONG J LEE
金额：
$ 7.83万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2019-12-01 至 2021-11-30
项目状态：
已结题

项目摘要

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.

抽象的卵巢癌（OVCA）在女性中癌症死亡中排名第五，占死亡人数比任何其他人数都多。妇科癌。每年，美国约有22,240名妇女将被诊断出患有OVCA，并且〜14,070将死亡。卵巢上皮癌占所有卵巢恶性肿瘤的90％。典型模式 OVCA的传播，也许是最早的转移是腹膜内传播，卵巢腹膜癌变病（OPC）。 OPC是OVCA的末端进化，被认为是致命的条件。在本赠款应用程序，我们假设一种多模式的方法（生化的组合试剂FC-Trail（免疫球蛋白FC结构域融合肿瘤坏死因子相关凋亡诱导的配体），化学治疗剂丝裂霉素C和轻度热疗）将有效防止 OPC复发通过促进凋亡死亡。该项目的具体目的是：（1）调查通过FC-TRAIL的组合治疗丝裂霉素C，丝裂霉素C的协同诱导细胞毒性的机理 OPC类器官中的高温；（2）建立人源化的PDX（患者衍生的Xenographogrotical）小鼠 OPC的模型并检查多模式方法的临床前结节效率。在第一个目标中，我们将采用生化和分子技术来研究凋亡死亡的机制 OPC类器官中的组合处理。在第二个目标中，我们将建立使用PDX肿瘤模型人源化三重转基因NSGTM-SGM3小鼠（非肥胖/严重的合并免疫缺陷表达人白细胞介素3的点数/scIDγ小鼠，粒细胞巨噬细胞刺激因子，和干细胞因子）并评估对组合治疗的反应。我们相信，由于NSG™ - SGM3小鼠是植入人类肿瘤以及人类建立的被证明的宿主造血干细胞移植后的免疫力，我们期望人源化的PDX小鼠模型保留原始肿瘤的大多数特征和重建的人类免疫系统。我们相信这项研究的成功结果将支持人源化PDX小鼠的有用应用模型评估这种新型基于嵌合的步道治疗，并将HIPEC治疗与患者 OPC。