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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

  1. Author:
    Gril, B.
    Palmieri, D.
    Qian, Y.
    Anwar, T.
    Ileva, L.
    Bernardo, M.
    Choyke, P.
    Liewehr, D. J.
    Steinberg, S. M.
    Steeg, P. S.

  2. Author Address

    [Gril, B; Palmieri, D; Qian, Y; Anwar, T; Steeg, PS] NCI, Womens Canc Sect, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Ileva, L; Bernardo, M] NCI, Lab Anim Sci Program, Sci Applicat Int Corp Frederick, Frederick, MD 21701 USA. [Bernardo, M; Choyke, P] NCI, Mol Imaging Program, Ctr Canc Res, Frederick, MD 21701 USA. [Liewehr, DJ; Steinberg, SM] NIH, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA.;Gril, B (reprint author), NCI, Womens Canc Sect, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA;grilbrun@mail.nih.gov
    1. Year: 2011
    2. Date: Oct
  2. Journal: Plos One
    1. 6
    2. 10
    3. Pages: 11
  4. Type of Article: Article
  5. Article Number: e25625
  6. ISSN: 1932-6203
  1. 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 B-Raf 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.

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External Sources

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  2. DOI: 10.1371/journal.pone.0025625
  3. View record in Web of Science®
  4. WOS: 000295966900037

Library Notes

  1. Fiscal Year: FY2011-2012
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