Show simple item record

dc.contributor.authorKodack, David P.
dc.contributor.authorChung, Euiheon
dc.contributor.authorYamashita, Hiroshi
dc.contributor.authorIncio, Joao
dc.contributor.authorDuyverman, Annique J.
dc.contributor.authorSong, Youngchul
dc.contributor.authorFarrar, Christian T.
dc.contributor.authorHuang, Yuhui
dc.contributor.authorAger, Eleanor
dc.contributor.authorKamoun, Walid
dc.contributor.authorGoel, Shom
dc.contributor.authorSnuderl, Matija
dc.contributor.authorLussiez, Alisha
dc.contributor.authorHiddingh, Lotte
dc.contributor.authorMahmood, Sidra
dc.contributor.authorTannous, Bakhos A.
dc.contributor.authorEichler, April F.
dc.contributor.authorFukumura, Dai
dc.contributor.authorEngelman, Jeffrey A.
dc.contributor.authorJain, Rakesh K.
dc.date.accessioned2019-10-13T16:02:54Z
dc.date.issued2012
dc.identifier.citationKodack, D. P., E. Chung, H. Yamashita, J. Incio, A. M. M. J. Duyverman, Y. Song, C. T. Farrar, et al. 2012. “Combined Targeting of HER2 and VEGFR2 for Effective Treatment of HER2-Amplified Breast Cancer Brain Metastases.” Proceedings of the National Academy of Sciences 109 (45): E3119–27. doi:10.1073/pnas.1216078109.
dc.identifier.issn0027-8424
dc.identifier.issn0744-2831
dc.identifier.issn1091-6490
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41542763*
dc.description.abstractBrain metastases are a serious obstacle in the treatment of patients with human epidermal growth factor receptor-2 (HER2)-amplified breast cancer. Although extracranial disease is controlled with HER2 inhibitors in the majority of patients, brain metastases often develop. Because these brain metastases do not respond to therapy, they are frequently the reason for treatment failure. We developed a mouse model of HER2-amplified breast cancer brain metastasis using an orthotopic xenograft of BT474 cells. As seen in patients, the HER2 inhibitors trastuzumab and lapatinib controlled tumor progression in the breast but failed to contain tumor growth in the brain. We observed that the combination of a HER2 inhibitor with an anti-VEGF receptor-2 (VEGFR2) antibody significantly slows tumor growth in the brain, resulting in a striking survival benefit. This benefit appears largely due to an enhanced antiangiogenic effect: Combination therapy reduced both the total and functional microvascular density in the brain xenografts. In addition, the combination therapy led to a marked increase in necrosis of the brain lesions. Moreover, we observed even better antitumor activity after combining both trastuzumab and lapatinib with the anti-VEGFR2 antibody. This triple-drug combination prolonged the median overall survival fivefold compared with the control-treated group and twofold compared with either two-drug regimen. These findings support the clinical development of this three-drug regimen for the treatment of HER2-amplified breast cancer brain metastases.
dc.language.isoen_US
dc.publisherNational Academy of Sciences
dash.licenseLAA
dc.titleCombined targeting of HER2 and VEGFR2 for effective treatment of HER2-amplified breast cancer brain metastases
dc.typeJournal Article
dc.description.versionVersion of Record
dc.relation.journalProceedings of the National Academy of Sciences of the United States of America
dash.depositing.authorFukumura, Dai::929b7d0391322bd39ce202f783b9a000::600
dc.date.available2019-10-13T16:02:54Z
dash.workflow.comments1Science Serial ID 90834
dc.identifier.doi10.1073/pnas.1216078109
dash.source.volume109;45
dash.source.pageE3119


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record