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.

摘要 腹膜假性粘液瘤（PMP）是一种潜在的，致命的恶性肿瘤， 全身化疗效果差，尽管进行了侵袭性、病态的局部手术， 疗法尽管已经报道了细胞减灭剂和抗肿瘤药物联合治疗的令人鼓舞的结果， 手术和腹腔热化疗（HIPEC），PMP复发是常见的。在这份赠款中， 应用中，我们假设多模式方法（生化试剂Fc-TRAIL的组合）， （免疫球蛋白Fc结构域融合的肿瘤坏死因子相关凋亡诱导配体）和铁蛋白 青蒿琥酯剂）可通过促进细胞凋亡来有效预防PMP的复发。的具体目标 该项目是：（1）检测使用Fc-TRAIL的组合治疗的临床前功效， 青蒿琥酯（ART）在PMP的小鼠腹膜内患者来源的异种移植物（PDX）模型中的作用;以及（2）研究 Fc-TRAIL和ART联合治疗在肿瘤细胞中协同诱导细胞毒性的机制 PMP的类器官第一个目标中的拟议研究将采用人源化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-SGM 3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 因素）。移植人造血干细胞（HSC）的NSGTM-SGM 3小鼠是研究造血干细胞的最新模型。 在体内环境中研究组合治疗对PMP肿瘤的临床疗效， 患者有风险。在第二个目标中，我们将采用生物化学和分子技术来研究 凋亡死亡的机制。由于NSG™-SGM 3小鼠是经证实的用于人肿瘤移植的宿主， 以及HSC移植后人免疫力的建立，我们期望人源化的HSC移植后， PDX小鼠模型将保留原始肿瘤和重建的人肿瘤的大部分特征。 免疫系统因此，本研究的成功结果将支持人源化PDX的应用 小鼠模型，以评估PMP患者的新型组合疗法。