Vandetanib shows potent efficacy against an EGFR dependent model of human lung cancer
Year: 2008
Session type: Poster / e-Poster / Silent Theatre session
Cancer and Infection Research Area, Astrazeneca, Macclesfield, Cheshire, UK
Abstract
Vandetanib (ZACTIMA™) is a tyrosine kinase inhibitor targeting VEGF-dependent angiogenesis and EGFR-dependent tumour cell proliferation. In this study we investigated the activity of vandetanib against a human NSCLC (PC-9) xenograft that has an activating EGFR mutation.
Nude mice bearing subcutaneous PC-9 xenografts were dosed with vehicle, vandetanib, gefitinib or vatalanib and the tumours were assessed for pharmcodynamic or growth inhibitory effects.
Vandetanib produced robust tumour regressions of PC-9 growth when compared to the control group. At identical doses, vandetanib and gefitinib effects were comparable. Vatalanib produced a modest but significant effect on tumour growth with no evidence of tumour regression. Ex vivo analysis of tumours showed significantly lower pEGFR levels and significantly higher M30 levels in vandetanib and gefitinib treated groups when compared to the vehicle group. In contrast, vatalanib treatment produced no significant effect on either pEGFR or M30 levels.
These results show that vandetanib, an inhibitor of VEGFR-2 and EGFR signalling, can exert a potent in vivo effect in the PC-9 model of human NSCLC. The effects of vandetanib were similar to those produced by a highly selective EGFR inhibitor (gefitinib), and markedly greater than the effects produced by a highly selective VEGFR-2 inhibitor (vatalanib). These data suggest that the effects of vandetanib in this model are primarily through inhibition of EGFR signalling, and clinical tumours that are highly sensitive to selective EGFR inhibitors may also be highly sensitive to vandetanib. Vandetanib is currently in Phase III trials, including a study (ZEST) comparing vandetanib with erlotinib in NSCLC.
Vandetanib (ZACTIMA™) is a tyrosine kinase inhibitor targeting VEGF-dependent angiogenesis and EGFR-dependent tumour cell proliferation. In this study we investigated the activity of vandetanib against a human NSCLC (PC-9) xenograft that has an activating EGFR mutation.
Nude mice bearing subcutaneous PC-9 xenografts were dosed with vehicle, vandetanib, gefitinib or vatalanib and the tumours were assessed for pharmcodynamic or growth inhibitory effects.
Vandetanib produced robust tumour regressions of PC-9 growth when compared to the control group. At identical doses, vandetanib and gefitinib effects were comparable. Vatalanib produced a modest but significant effect on tumour growth with no evidence of tumour regression. Ex vivo analysis of tumours showed significantly lower pEGFR levels and significantly higher M30 levels in vandetanib and gefitinib treated groups when compared to the vehicle group. In contrast, vatalanib treatment produced no significant effect on either pEGFR or M30 levels.
These results show that vandetanib, an inhibitor of VEGFR-2 and EGFR signalling, can exert a potent in vivo effect in the PC-9 model of human NSCLC. The effects of vandetanib were similar to those produced by a highly selective EGFR inhibitor (gefitinib), and markedly greater than the effects produced by a highly selective VEGFR-2 inhibitor (vatalanib). These data suggest that the effects of vandetanib in this model are primarily through inhibition of EGFR signalling, and clinical tumours that are highly sensitive to selective EGFR inhibitors may also be highly sensitive to vandetanib. Vandetanib is currently in Phase III trials, including a study (ZEST) comparing vandetanib with erlotinib in NSCLC.
