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PNAS 109 (45): 3119-3127

Copyright © 2012 by the National Academy of Sciences.

PNAS Plus


PNAS PLUS / BIOLOGICAL SCIENCES / MEDICAL SCIENCES

Combined targeting of HER2 and VEGFR2 for effective treatment of HER2-amplified breast cancer brain metastases

David P. Kodacka,1, Euiheon Chunga,b,1, Hiroshi Yamashitaa,1, Joao Incioa, Annique M. M. J. Duyvermana, Youngchul Songc, Christian T. Farrard, Yuhui Huanga, Eleanor Agera, Walid Kamouna, Shom Goela, Matija Snuderla,e, Alisha Lussieza, Lotte Hiddingha, Sidra Mahmooda, Bakhos A. Tannousf, April F. Eichlerg, Dai Fukumuraa,2, Jeffrey A. Engelmanc,2, and Rakesh K. Jaina,2

aEdwin L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, cDepartment of Medicine, dMartinos Center for Biomedical Imaging, eDepartment of Pathology, fDepartment of Neurology, and gStephen E. and Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; and bDepartment of Medical System Engineering and School of Mechatronics, Gwangju Institute of Science and Technology, Gwangju 500-712, South Korea

2To whom correspondence may be addressed. E-mail: dai{at}steele.mgh.harvard.edu, jengelman{at}partners.org, or jain{at}steele.mgh.harvard.edu.

Abstract: Brain 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.

Key Words: treatment resistance • tumor–stroma interaction • targeted therapy • tumor microenvironment • antiangiogenesis


 

Freely available online through the PNAS open access option.

Conflict of interest statement: J.A.E. serves as a consultant for GlaxoSmithKline and Genentech (Roche). R.K.J. has research grants from Dyax, MedImmune, and Roche; serves as a consultant to Noxxon Pharmaceuticals; serves on the Scientific Advisory Board of Enlight and SynDevRx; serves on the Board of Directors of XTuit; serves on the Board of Trustees of H&Q Healthcare Investors and H&Q Life Sciences Investors; and has equity in Enlight, SynDevRx, and XTuit Pharmaceuticals. No funds or reagents from any of these organizations were used in the current study.

This is a Contributed submission.

See full research article on page E3119 of www.pnas.org.

Cite this Author Summary as: PNAS 10.1073/pnas.1216078109.


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