Application of in vivo humanized PDX mouse model and ex vivo organoid model to assess the therapeutic efficacy of combinatorial therapy for pseudomyxoma peritonei

摘要 摘要腹膜假性黏液瘤(PMP)起源于阑尾，是一种隐匿性、致死性的恶性肿瘤。 全身化疗效果差，尽管进行了积极的、病态的局部手术，但经常复发 心理治疗。尽管已经报道了细胞减少剂联合应用的令人鼓舞的治疗结果 手术和热疗(HIPEC)后，PMP复发较常见。在这笔赠款中 应用，我们假设多模式方法(生化试剂FC-TRAIL的组合 (免疫球蛋白Fc结构域融合肿瘤坏死因子相关的凋亡诱导配体)和铁链 青蒿琥酯)可通过促进细胞凋亡性死亡，有效预防PMP复发。的具体目标 本项目旨在：(1)用FC-TRAIL和TRAIL检测联合治疗的临床前疗效。 青蒿琥酯(ART)对小鼠腹膜PMP患者来源的异种移植(PDX)模型的影响；以及(2)研究 联合应用FC-TRAIL和ART协同诱导肿瘤细胞毒作用的机制 PMP的有机化合物。第一个目标中提出的研究将使用人源化的PDX小鼠模型来评估 多模式治疗对PMP患者PDX肿瘤生长和消退的影响 人源化三重转基因NSGTM-SGM3小鼠(非肥胖型糖尿病/严重联合免疫缺陷 表达人白介素3、粒细胞巨噬细胞集落刺激因子和干细胞的伽马小鼠 因数)。移植了人造血干细胞(HSC)的NSGTM-SGM3小鼠是治疗 体内不放置联合治疗PMP肿瘤的临床疗效研究 病人处于危险之中。在第二个目标中，我们将使用生化和分子技术来研究 细胞凋亡性死亡机制。由于nsg™-sgm3小鼠已被证实是移植人类肿瘤的宿主 以及造血干细胞移植后人类免疫力的建立，我们预计人源化 PDX小鼠模型将保留原始肿瘤和重组人的大部分特征 免疫系统。因此，本研究的成功结果将为人性化PDX的应用提供支持 评估一种治疗PMP患者的新组合疗法的小鼠模型。

ABSTRACT Pseudomyxoma peritonei (PMP) of appendiceal origin is an insidious, lethal malignancy that responds poorly to systemic chemotherapy and frequently recurs despite aggressive, morbid locoregional surgical therapy. Although encouraging treatment results have been reported with the combination of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC), PMP recurrence is common. 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) and the ferroptotic agent artesunate) will effectively prevent recurrence of PMP by promoting apoptotic death. The specific aims of this project are to: (1) examine the preclinical efficacy of the combinatorial treatment using Fc-TRAIL and artesunate (ART) in mouse intraperitoneal patient-derived xenograft (PDX) models of PMP; and (2) investigate the mechanism of synergistic induction of cytotoxicity by the combinatorial treatment of Fc-TRAIL and ART in organoids of PMP. The proposed studies in the first aim will employ humanized PDX mouse models to assess the effect of the multimodal treatment on the growth and regression of PDX tumors from PMP patients in humanized triple transgenic NSGTM-SGM3 mice (nonobese diabetic/severe combined immunodeficiency gamma mice expressing human interleukin-3, granulocyte-macrophage colony-stimulating factor and stem cell factor). NSGTM-SGM3 mice engrafted with human hematopoietic stem cells (HSC) are cutting-edge models for studying the clinical efficacy of combinatorial treatment on PMP tumor in an in vivo setting without placing patients at risk. In the second aim, we will employ biochemical and molecular techniques to investigate the mechanism of apoptotic death. Since NSG™-SGM3 mice are a proven host for engraftment of human tumors as well as the establishment of human immunity following HSC transplantation, we expect that humanized PDX mouse models will retain most of the characteristics of the original tumors and reconstituted human immune system. Thus, the successful outcome of this study will support the application of the humanized PDX mouse model to assess a novel combinatorial therapy for patients with PMP.