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

Award Number: R21CA259243
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $191,278 )
2023	2023	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Treatment Research	004	2	9/15/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$162,487
2023	2023	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Treatment Research	001	2	3/30/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$191,278
2023	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Treatment Research	003	1	9/15/2023	NEW	-$162,487
2023	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Treatment Research	000	1	3/30/2023	NEW	$0
2023	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Treatment Research	002	1	4/5/2023	NEW	$0
														Subtotal = $191,278

Issue Date FY: 2022 ( Subtotal = $220,953 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Treatment Research	000	1	12/20/2021	NEW	$220,953
														Subtotal = $220,953

Grand Total All Awards = $412,231

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

Award Number: R21CA259243

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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