Abstract
Abstract Brain metastases occur in approximately 35% of metastatic breast cancer patients whose tumors overexpress HER2. Using a quantitative model system to study breast cancer brain metastasis, HER2 overexpression increased the brain colonization of a brain seeking subline of MDA-MB-231 cells (231-BR-HER2). Since HER2 has been shown to induce overexpression of VEGF, we hypothesized that the anti-angiogenic drug pazopanib would reduce the metastatic outgrowth of breast cancer cells in the brain. Pazopanib is a multispecific tyrosine kinase inhibitor targeting VEGFR-1, -2, and -3, PDGFR alpha and beta, and c-kit. We previously showed that pazopanib directly targets the tumor cell through the disruption of B-Raf pathway. Pazopanib prevented the outgrowth of 231-BR-HER2 large brain metastasis by 73% (p<0.0001). Metastasis has been described as an interaction of tumor cells and their environment. Here we evaluated the effect of pazopanib on the brain neuro-inflammatory microenvironment. Previously, activated microglia and activated GFAP-expression astrocytes were observed around and within experimental brain metastases as well as from resected human brain metastases of breast cancer. In our experiments, the 231-BR-HER2 cell line was injected into the left cardiac ventricle of immunocompromised mice; mice were treated with vehicle, 30mg/kg or 100mg/kg pazopanib twice a day beginning on day 3 post-injection. Brain metastases were counted using H&E staining and brain slides were immunostained with markers for brain micro-environment components. In the brain metastases, using an antibody to the phosphorylation site tyrosine 751 of PDGFR beta, a subpopulation of GFAP+ astrocytes was observed, previously undescribed. P-PDGFR beta + astrocytes were only detected around the brain metastases, suggesting a specific activation of astrocytes by tumor cells. Pazopanib treatment resulted in a trend, 76% (p=0.13) and 80% (p=0.070) decrease of the pY751 PDGFR beta + astrocyte population, at 30 and 100mg/kg respectively. In contrast, Pazopanib did not have any effect on NG2+pericyte, collagen IV or microglia expression. The data suggest a specific effect of pazopanib on the brain microenvironment. Collectively, the data identify an effect of pazopanib on the brain microenvironment, as well as tumor cells, which makes this drug an interesting candidate for brain metastasis prevention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3561. doi:10.1158/1538-7445.AM2011-3561
Published Version
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