The B-Raf Status of Tumor Cells May Be a Significant Determinant of Both Antitumor and Anti-Angiogenic Effects of Pazopanib in Xenograft Tumor Models
Abstract
Pazopanib is an FDA approved Vascular Endothelial Growth Factor Receptor inhibitor. We previously reported that it also inhibits tumor cell B-Raf activity in an experimental brain metastatic setting. Here, we determine the effects of different BRaf genotypes on pazopanib efficacy, in terms of primary tumor growth and anti-angiogenesis. A panel of seven human breast cancer and melanoma cell lines harboring different mutations in the Ras-Raf pathway was implanted orthotopically in mice, and tumor growth, ERK1/2, MEK1/2 and AKT activation, and blood vessel density and permeability were analyzed. Pazopanib was significantly inhibitory to xenografts expressing either exon 11 mutations of B-Raf, or HER2 activated wild type B-Raf; no significant inhibition of a xenograft expressing the common V600E B-Raf mutation was observed. Decreased pMEK staining in the responsive tumors confirmed that B-Raf was targeted by pazopanib. Interestingly, pazopanib inhibition of tumor cell B-Raf also correlated with its anti-angiogenic activity, as quantified by vessel density and area. In conclusion, using pazopanib, tumor B-Raf status was identified as a significant determinant of both tumor growth and angiogenesis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 05, 2011
- Accession Number
- ADA551031
Entities
People
- Brunilde Gril
- David J. Liewehr
- Diane Palmieri
- Lilia Ileva
- Marcelino Bernardo
- Patricia Steeg
- Peter L Choyke
- Seth M Steinberg
- Talha Anwar
- Yong Qian
Organizations
- National Cancer Institute