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.