Treatment with BLU9931 leads to tumor regression in the FGF19-overexpressing PDX-derived xenograft LIXC012. Treatment with BLU9931 leads to tumor regression.

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Treatment with BLU9931 leads to tumor regression in the FGF19-overexpressing PDX-derived xenograft LIXC012. Treatment with BLU9931 leads to tumor regression in the FGF19-overexpressing PDX-derived xenograft LIXC012. A, FGFR4 signaling was examined in LIXC012 tumors following twice-daily treatment with BLU9931 at indicated doses for a total of 4 doses. LIXC012 tumors were harvested at indicated times following the last dose. CYP7A1 mRNA levels were determined using qRT-PCR and are expressed relative to levels in tumors from vehicle-treated mice (3 mice/group). The concentration of BLU9931 in plasma is expressed for each time point in ng/mL. Of note, the high level of CYP7A1 message in the 30-mg/kg BLU9931 group harvested 24 hours following the last dose is not consistent with BLU9931 plasma levels or with Ki-67 positivity and is likely an aberrant data point. B, BLU9931 inhibits expression of the proliferative marker Ki-67. Representative photomicrographs (40× magnification) of LIXC012 tumors collected at indicated times following the last dose. Bar graph, mean ± SD percent cells positive for Ki-67 for three independent tumors from each treatment group. C, in vivo antitumor efficacy of BLU9931 in LIXC012 tumors. BLU9931 was administered orally (po), twice daily (bid), at the indicated doses (9 mice/group). Sorafenib was administered orally once daily (qd) at 40 mg/kg. Data, mean ± SEM. D, body weight was monitored during treatment with BLU9931 and sorafenib. Data are expressed as a percentage of body weight at the initiation of treatment and are plotted as mean ± SEM. Margit Hagel et al. Cancer Discovery 2015;5:424-437 ©2015 by American Association for Cancer Research