Oral Presentation 14th International Biennial Conference on Metastasis Research 2012

Targeting Src family kinases as novel therapies for breast cancer brain metastases (#3)

Dihua Yu 1
  1. The University of Texas MD Anderson Cancer Center, Houston, TX, United States

Among 1.3 million women diagnosed with breast cancer every year, about 10-16% develop brain metastases. Despite the better control of primary tumor and improved overall survival of breast cancer patients, the incident of developing life-threatening brain metastasis is increasing. At present, no effective drug treatment exists for patients with refractory breast cancer metastatic to the brain. Therefore, novel and effective therapeutic approaches are urgently needed for this population. Unfortunately, developing effective therapeutics for brain metastasis is largely hampered by a lack of in-depth understanding of the basic mechanisms of brain metastasis. Here, we reveal a critical role of Src activation in promoting breast cancer brain metastasis and tested Src-targeting combinatorial regimen for preventing and treating brain metastases. Src is hyper-activated in brain-seeking human breast cancer cell lines and patients’ brain metastasis tumors. Mechanistically, Src activation in tumor cells promoted tumor cell extravasation into the brain parenchyma via permeabilization of the blood-brain barrier. When coupled with an EGFR/HER2-dual-targeting agent lapatinib, a clinically applicable Src-targeting exhibited a significant pre-clinical efficacy in preventing the outgrowth of disseminated breast cancer cells through induction of cell cycle arrest. More importantly, the combinatorial treatment also significantly inhibited established experimental brain metastases and prolonged survival of metastases-bearing mice (p=0.004, log-rank survival test). Our results highlight a highly promising, clinically applicable, Src-targeting regimen for breast cancer patients suffering brain metastasis. Ultimately, our findings could be translated to clinical trials as new therapies for breast cancer patients with brain metastasis.

Siyuan Zhang1,2, Wen-Chien Huang1,2, Chenyu Zhang1, Frank J. Lowery1, Lin Zhang1, Patricia S. Steeg3, Dihua Yu1

1Departments of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA, 3Women’s Cancers Section, National Cancer Institute, USA, 2These authors contributed equally to this work.