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

应用体内人源化PDX小鼠模型和离体类器官模型评估腹膜假粘液瘤联合治疗的疗效

• 批准号: 10356993
• 负责人: YONG J LEE
• 金额: $ 22.1万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-20 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356993
• 关键词: 3-Dimensional; Antineoplastic Agents; Apoptosis; Apoptotic; Applications Grants; Biochemical; Biological; Carcinomatosis; Cells; Cellularity; Cessation of life; Characteristics; Chimeric Proteins; Classification; Combined Modality Therapy; Consensus; Disease; Drug Kinetics; Engraftment; FDA approved; Fc Immunoglobulins; Fc domain; Goblet Cells; Granulocyte-Macrophage Colony-Stimulating Factor; Greater sac of peritoneum; Growth; Half-Life; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hepatotoxicity; Human; Immune system; Immunity; Institutes; Interleukins; Intestinal Obstruction; Intravenous Bolus; Lead; Ligands; Malignant Neoplasms; Medical center; Microscopic; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mucinous; Mucins; Mus; Non obese; Normal Cell; Nutritional; Operative Surgical Procedures; Organoids; Outcome Study; Patients; Peritoneal; Persons; Plasma; Positioning Attribute; Postoperative Period; Procedures; Prognosis; Proteins; Pseudomyxoma Peritonei; Recurrence; Regimen; Reporting; Residual Tumors; Residual state; Risk; Serum; Severe Combined Immunodeficiency; Signal Pathway; Stem Cell Factor; Study models; System; TNF gene; TNFSF10 gene; Techniques; Testing; Therapeutic; Therapeutic Agents; Transgenic Organisms; Treatment Efficacy; Tumor Debulking; Tumor Tissue; Universities; Xenograft procedure; advanced disease; anti-cancer; artesunate; base; biological adaptation to stress; cancer cell; chemotherapy; clinical efficacy; combinatorial; cytotoxicity; diabetic; endoplasmic reticulum stress; gastrointestinal system; improved; in vitro activity; in vivo; intraperitoneal; intraperitoneal therapy; mortality; mouse model; multimodality; novel; novel strategies; partial response; patient derived xenograft model; preclinical efficacy; pressure; prevent; rare cancer; receptor; reconstitution; response; sensor; tumor; tumor xenograft

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.

抽象的 起源于阑尾的腹膜假粘液瘤 (PMP) 是一种阴险、致命的恶性肿瘤， 全身化疗效果不佳，尽管进行了激进的、病态的局部手术，但仍经常复发 尽管已经报道了与细胞减灭术相结合的令人鼓舞的治疗结果。 手术和腹腔热灌注化疗（HIPEC）后，PMP 复发在本次资助中很常见。 应用中，我们采用了多模式方法（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凋亡诱导配体）和铁死亡 青蒿琥酯）通过促进细胞凋亡来有效预防PMP的复发。 该项目的目的是：（1）检查使用 Fc-TRAIL 组合治疗的临床前疗效和 青蒿琥酯（ART）在小鼠腹腔内患者来源的 PMP 异种移植（PDX）模型中的作用；（2）研究 Fc-TRAIL和ART联合治疗协同诱导细胞毒性的机制 第一个目标中拟议的研究将采用人源化 PDX 小鼠模型来评估 PMP 的器官。 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和干细胞的γ小鼠 移植了人类造血干细胞 (HSC) 的 NSGTM-SGM3 小鼠是最先进的模型。 研究在体内环境中联合治疗 PMP 肿瘤的临床疗效，无需放置 在第二个目标中，我们将采用生化和分子技术来研究处于危险中的患者。 由于 NSG™-SGM3 小鼠是人类肿瘤移植的宿主。 以及HSC移植后人体免疫力的建立，我们期望人源化 PDX小鼠模型将保留原始肿瘤和重组人类的大部分特征 因此，本研究的成功结果将支持人源化PDX的应用。 小鼠模型来评估 PMP 患者的新型组合疗法。