HER2 Support Group Forums - View Single Post - I strongly recommend you read this article (even if you have to struggle a bit)

Lani · 06-22-2012, 06:01 AM

http://www.plosone.org/article/info%...l.pone.0039626

incredible advance in understanding and fabulous results even in Stage IV even with brain mets or leptomeningeal mets, whether ER+ or ER-

Hope this speeds up drug development and testing and leads to both cure/prevention!

Open Access
RESEARCH ARTICLE
Multiorgan Metastasis of Human HER-2+ Breast Cancer in Rag2−/−;Il2rg−/− Mice and Treatment with PI3K Inhibitor

Patrizia Nanni1, Giordano Nicoletti2, Arianna Palladini1, Stefania Croci1, Annalisa Murgo1, Marianna L. Ianzano1, Valentina Grosso1, Valeria Stivani1, Agnese Antognoli1, Alessia Lamolinara3, Lorena Landuzzi2, Emmanuelle di Tomaso4, Manuela Iezzi3, Carla De Giovanni1*, Pier-Luigi Lollini5
1 Section of Cancer Research, Department of Experimental Pathology, University of Bologna, Bologna, Italy, 2 Rizzoli Orthopedic Institute, Bologna, Italy, 3 Aging Research Centre, “G. D'Annunzio” University, Chieti, Italy, 4 Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts, United States of America, 5 Department of Hematology and Oncological Sciences, University of Bologna, Bologna, Italy
Abstract
In vivo studies of the metastatic process are severely hampered by the fact that most human tumor cell lines derived from highly metastatic tumors fail to consistently metastasize in immunodeficient mice like nude mice. We describe a model system based on a highly immunodeficient double knockout mouse, Rag2−/−;Il2rg−/−, which lacks T, B and NK cell activity. In this model human metastatic HER-2+ breast cancer cells displayed their full multiorgan metastatic potential, without the need for selections or additional manipulations of the system. Human HER-2+ breast cancer cell lines MDA-MB-453 and BT-474 injected into Rag2−/−;Il2rg−/− mice faithfully reproduced human cancer dissemination, with multiple metastatic sites that included lungs, bones, brain, liver, ovaries, and others. Multiorgan metastatic spread was obtained both from local tumors, growing orthotopically or subcutaneously, and from cells injected intravenously. The problem of brain recurrencies is acutely felt in HER-2+ breast cancer, because monoclonal antibodies against HER-2 penetrate poorly the blood-brain barrier. We studied whether a novel oral small molecule inhibitor of downstream PI3K, selected for its penetration of the blood-brain barrier, could affect multiorgan metastatic spread in Rag2−/−; Il2rg−/− mice. NVP-BKM120 effectively controlled metastatic growth in multiple organs, and resulted in a significant proportion of mice free from brain and bone metastases. Human HER-2+ human breast cancer cells in Rag2−/−;Il2rg−/− mice faithfully reproduced the multiorgan metastatic pattern observed in patients, thus allowing the investigation of metastatic mechanisms and the preclinical study of novel antimetastatic agents.

06-22-2012, 06:01 AM	#1
Lani Senior Member Join Date: Mar 2006 Posts: 4,778	I strongly recommend you read this article (even if you have to struggle a bit) http://www.plosone.org/article/info%...l.pone.0039626 incredible advance in understanding and fabulous results even in Stage IV even with brain mets or leptomeningeal mets, whether ER+ or ER- Hope this speeds up drug development and testing and leads to both cure/prevention! Open Access RESEARCH ARTICLE Multiorgan Metastasis of Human HER-2+ Breast Cancer in Rag2−/−;Il2rg−/− Mice and Treatment with PI3K Inhibitor Patrizia Nanni1, Giordano Nicoletti2, Arianna Palladini1, Stefania Croci1, Annalisa Murgo1, Marianna L. Ianzano1, Valentina Grosso1, Valeria Stivani1, Agnese Antognoli1, Alessia Lamolinara3, Lorena Landuzzi2, Emmanuelle di Tomaso4, Manuela Iezzi3, Carla De Giovanni1*, Pier-Luigi Lollini5 1 Section of Cancer Research, Department of Experimental Pathology, University of Bologna, Bologna, Italy, 2 Rizzoli Orthopedic Institute, Bologna, Italy, 3 Aging Research Centre, “G. D'Annunzio” University, Chieti, Italy, 4 Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts, United States of America, 5 Department of Hematology and Oncological Sciences, University of Bologna, Bologna, Italy Abstract In vivo studies of the metastatic process are severely hampered by the fact that most human tumor cell lines derived from highly metastatic tumors fail to consistently metastasize in immunodeficient mice like nude mice. We describe a model system based on a highly immunodeficient double knockout mouse, Rag2−/−;Il2rg−/−, which lacks T, B and NK cell activity. In this model human metastatic HER-2+ breast cancer cells displayed their full multiorgan metastatic potential, without the need for selections or additional manipulations of the system. Human HER-2+ breast cancer cell lines MDA-MB-453 and BT-474 injected into Rag2−/−;Il2rg−/− mice faithfully reproduced human cancer dissemination, with multiple metastatic sites that included lungs, bones, brain, liver, ovaries, and others. Multiorgan metastatic spread was obtained both from local tumors, growing orthotopically or subcutaneously, and from cells injected intravenously. The problem of brain recurrencies is acutely felt in HER-2+ breast cancer, because monoclonal antibodies against HER-2 penetrate poorly the blood-brain barrier. We studied whether a novel oral small molecule inhibitor of downstream PI3K, selected for its penetration of the blood-brain barrier, could affect multiorgan metastatic spread in Rag2−/−; Il2rg−/− mice. NVP-BKM120 effectively controlled metastatic growth in multiple organs, and resulted in a significant proportion of mice free from brain and bone metastases. Human HER-2+ human breast cancer cells in Rag2−/−;Il2rg−/− mice faithfully reproduced the multiorgan metastatic pattern observed in patients, thus allowing the investigation of metastatic mechanisms and the preclinical study of novel antimetastatic agents.