Abstract C193: Biological evaluation of novel multi‐targeted Aurora‐B kinase inhibitor TAK‐901 in xenograft models
Molecular Cancer Therapeutics(2009)
Abstract
Aurora kinases play an essential role in cell division, specifically orchestrating several intricate steps during the mitotic phase of the cell cycle. The human genome encodes for 3 Aurora kinase genes, designated Aurora A, B, and C. Aurora A localizes to centrosomes and spindle poles and is required for mitotic spindle assembly, whereas Aurora B is a chromosome passenger protein required for phosphorylation of histone H3, chromosome segregation, and cytokinesis. Expression levels of Aurora A and B kinases are frequently elevated in human cancers making them attractive targets for therapeutic intervention. TAK‐901 is an Aurora B kinase inhibitor with multi‐targeted inhibitory activity against other kinases important in malignancy. In the present study, we investigated the pharmacodynamic effects and in vivo activity of TAK‐901 in human tumor xenograftmodels. In solid tumor xenograft models, potent dose‐dependent antitumor activity was observed against HCT116 (colon), H460 (large cell lung) and A2780 (ovary) cancer models by twice daily intravenous dosing on 2 consecutive days per week for 3 cycles. TAK‐901 also displayed potent activity against several leukemia models such as subcutaneously implanted MV4‐11 and HL60 (AML). In the A2780, HCT116, and HL60 models, TAK‐901 induced tumor regression at higher dose levels, including complete regression of A2780 tumors at 30 and 45 mg/kg/injection. When dosed in combination with chemotherapeutic agents, such as irinotecan in the HCT116 model or daunorubicin in the HL60 model, TAK‐901 produced additive effects. Following intravenous administration of 20 and 40 mg/kg TAK‐901 in the A2780 xenograft model, histone H3 phosphorylation was completely suppressed for at least 6 hours and in the 40 mg/kg treated tumors did not return to control levels during the 12 hour time course. After multiple doses of TAK‐901, polyploidy was observed in the tumor samples. TAK‐901 drug levels remained constant throughout the time course in tumor tissues whereas plasma levels declined steadily. These in vivo biomarker studies demonstrate that TAK‐901 induces pharmacodynamic responses consistent with Aurora B kinase inhibition, which correlates with effective retention of TAK 901 in tumor tissues. Taken together, these preclinical data emphasize the therapeutic potential of TAK‐ 901 in the treatment of diverse human malignancies. TAK‐901 is currently under investigation in Phase I clinical trials. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C193.
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Key words
kinase,inhibitor,abstract c193
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