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• W2149664078 abstract "Tivozanib (AV‐951 or KRN951) is an ATP competitive small molecule VEGFR antagonist that exhibits picomolar inhibitory activity against all three VEGF receptors. It has demonstrated robust clinical activity in renal cell carcinoma and is currently being evaluated in multiple clinical studies including a monotherapy phase 1b/2a trial in NSCLC. NSCLC is a highly heterogeneous disease, in which tumor histology and genetics have defined sensitivities and settings to targeted therapeutics. To model and explore potential clinical settings, we created genetically engineered lung adenocarcinoma models driven by EGFRL858R, EGFRL858R/T790M or KRAS G12V, propagated these models in vivo both subcutaneously and orthotopically and evaluated tumor inhibitory activity of tivozanib as a single agent or in combination with EGFR inhibitor erlotinib. To further explore activity of metastatic lesions to the lung, we also evaluated the activity of tivozanib using an engineered breast tumor metastatic model. Treatment of subcutaneous lung KRAS tumors or lung EGFRL858R/T790M tumors with tivozanib alone resulted in complete tumor growth inhibition. Histological analysis revealed substantial central necrosis with proliferating (Ki67+) tumor cells present only at the tumor periphery, typical of an anti‐angiogenesis mechanism. When tivozanib was given to treat lung EGFRL858R+T790M tumors in an orthotopic setting in the lungs after tumors were well established, significant antiangiogenic and antitumor effects, as demonstrated by histology and extended survival period, were observed. However, the necrotic lung lesions showed no sign of resorption or elimination after 6 weeks of treatment. Similar results were also observed in a HER2 driven breast tumor lung metastatic model. This prompted us to further explore the activity of tivozanib in an orthotopic lung tumor minimal disease model. Tivozanib treatment in this setting did not alter tumor lesion numbers but effectively blocked the progression of micro pre‐angiogenic lesions. Finally, we explored the combined activity of tivozanib and erlotinib in a model constructed to reflect the emergence of erlotinib resistance by implanting tumor material comprising both EGFRL858R and EGFRL858R/T790M tumor cells. In this setting, the combination of tivozanib and erlotinib resulted in significantly greater control of tumor progression than erlotinib alone. Our results suggest that tivozanib may have activity as a single agent in lung tumors with KRAS or EGFR L858R/T790M mutations and that combinations with other targeted lung cancer drugs such as erlotinib may provide meaningful clinical benefit. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A255." @default.
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• W2149664078 date "2009-12-10" @default.
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• W2149664078 title "Abstract A255: Activity of VEGFR inhibitor tivozanib as a single agent or in combination with EGFR inhibitor erlotinib in engineered lung adenocarcinoma models" @default.
• W2149664078 doi "https://doi.org/10.1158/1535-7163.targ-09-a255" @default.
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