Abstract 2974: Combating breast cancer brain metastasis by targeting Src family kinases

Abstract

Abstract Background: Among 1.3 million women diagnosed with breast cancer every year, 10-16% will develop brain metastases. The median survival of patients with brain metastases is less than one year. A most challenging problem is no effective treatment for patients with refractory metastatic breast cancer to the brain. Therefore, novel and effective therapeutic approaches are urgently needed for this population. Recently, our retrospective analyses revealed a significant up-regulation of Src family kinase (SFK) in breast cancer brain metastasis lesions compared with primary tumors. Additionally, HER2-overexpressing breast cancers with Src activation have a higher incidence of brain metastasis. Thus, we hypothesize that activation of SFK plays a critical role in promoting breast cancer brain metastasis. Aims and Methodology: The major aims of this project are: 1) study the role of Src activation in breast cancer brain metastasis; 2) investigate the pre-clinical efficacy of combination Src inhibitor and HER2-targeting therapy Lapatinib in treatment of brain metastasis. We used HER2-overexpressing breast cancer cell line models, in vitro assays of metastasis-properties, and in vivo brain metastasis mouse model (intracarotid artery injection) to test our hypothesis. Results and Conclusions: Src activity is up-regulated in both brain-seek cells lines and human brain metastasis tumors when compared to either parental cells lines or primary breast cancers respectively. To test the role of Src activation in brain metastasis, we established stable cells lines with constitutive-activation of Src. The Src activation enhanced the tumor cell trans-blood brain barrier migration in vitro. Src activation in cells led to a higher brain metastasis incidence in vivo after intracarotid artery injection. We treated Src-activated brain metastasis in vivo with a Src inhibitor saracatinib, a drug under Phase II clinical trial. This Src-targeting treatment decreased the overall incidence of brain metastasis. Combining sarcatinib with EGFR-HER2 dual-targeting agent lapatinib further prolonged the overall survival of tumor bearing mice and significantly inhibited both micro- and macro-metastasis. In summary, novel SFK targeting regimens may be developed as promising therapies for breast cancer patients with brain metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2974. doi:1538-7445.AM2012-2974