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; 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 阑尾起源的腹膜腹膜（PMP）是一种阴险的致命恶性肿瘤，反应 全身化疗不足，并且经常复发绝望的攻击性，病态局部外科手术 治疗。尽管已经报道了令人鼓舞的治疗结果 手术和高温腹膜内化疗（HIPEC），PMP复发很常见。在这笔赠款中 应用，我们假设一种多模式方法（生化剂FC-Trail的组合 （免疫球蛋白FC结构域融合了肿瘤坏死因子与凋亡诱导的配体）和铁铁蛋白 临时工敏于临时，将通过促进凋亡死亡来有效防止PMP复发。具体目的 该项目是：（1）使用FC-Trail和 PMP的小鼠腹膜内患者衍生的Xenographic（PDX）模型中的小鼠（ART）； （2）调查 通过对FC-Trail和Art的组合处理，在诱导细胞毒性的机制 PMP的类器官。第一个目标中提出的研究将采用人源化的PDX小鼠模型评估 多模式治疗对PMP患者PDX肿瘤生长和回归的影响 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的伽马小鼠，粒细胞 - 巨噬细胞群刺激因子和干细胞 因素）。植入人类造血干细胞（HSC）的NSGTM-SGM3小鼠是尖端的模型 研究在体内环境中对PMP肿瘤组合治疗的临床效率而不放置 有风险的患者。在第二个目标中，我们将采用生化和分子技术来研究 凋亡死亡的机制。由于NSG™-SGM3小鼠是人类肿瘤植入的宿主 除了HSC移植后建立人类免疫力，我们期望人性化 PDX鼠标模型将保留原始肿瘤的大多数特征并重构人类 免疫系统。这是这项研究的成功结果将支持人源化PDX的应用 小鼠模型评估PMP患者的新型组合治疗。