A novel immunogenic mouse model of melanoma for the preclinical assessment of combination targeted and immune-based therapy.

Autor: Lelliott EJ; Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia., Cullinane C; Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia., Martin CA; Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Walker R; Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Ramsbottom KM; Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Souza-Fonseca-Guimaraes F; Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.; Division of Molecular Immunology, The Walter Eliza Hall Institute of Medical Research, Parkville, VIC, Australia., Abuhammad S; Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Michie J; Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia., Kirby L; Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Young RJ; Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Slater A; Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Lau P; Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia., Meeth K; Department of Pathology, Yale University School of Medicine, New Haven, CT, USA., Oliaro J; Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia., Haynes N; Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.; Department of Pathology, University of Melbourne, Melbourne, VIC, Australia., McArthur GA; Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.; Department of Medicine, St Vincent's Hospital, University of Melbourne, Melbourne, VIC, Australia., Sheppard KE; Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. karen.sheppard@petermac.org.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. karen.sheppard@petermac.org.; Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia. karen.sheppard@petermac.org.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2019 Feb 04; Vol. 9 (1), pp. 1225. Date of Electronic Publication: 2019 Feb 04.
DOI: 10.1038/s41598-018-37883-y
Abstrakt: Both targeted therapy and immunotherapy have been used successfully to treat melanoma, but the development of resistance and poor response rates to the individual therapies has limited their success. Designing rational combinations of targeted therapy and immunotherapy may overcome these obstacles, but requires assessment in preclinical models with the capacity to respond to both therapeutic classes. Herein, we describe the development and characterization of a novel, immunogenic variant of the Braf V600E Cdkn2a -/- Pten -/- YUMM1.1 tumor model that expresses the immunogen, ovalbumin (YOVAL1.1). We demonstrate that, unlike parental tumors, YOVAL1.1 tumors are immunogenic in vivo and can be controlled by immunotherapy. Importantly, YOVAL1.1 tumors are sensitive to targeted inhibitors of BRAF V600E and MEK, responding in a manner consistent with human BRAF V600E melanoma. The YOVAL1.1 melanoma model is transplantable, immunogenic and sensitive to clinical therapies, making it a valuable platform to guide strategic development of combined targeted therapy and immunotherapy approaches in BRAF V600E melanoma.
Databáze: MEDLINE
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