AZD2171 is a highly potent (IC50 <1 nM), orally active, vascular endothelial growth factor (VEGF) signaling inhibitor. The compound has been shown to inhibit VEGF receptor (VEGFR) tyrosine kinase activity in vitro, and prevent physiological and pathological angiogenesis in vivo. Consistent with this activity, once-daily oral administration of AZD2171 (≥1.5 mg/kg) significantly inhibits the growth of histologically diverse human tumor xenografts. These data have prompted clinical examination of this agent as a once-daily oral cancer therapy. In addition to potential activity from inhibiting VEGF signaling alone, a number of preclinical studies have suggested that VEGF signaling blockade may provide additional benefit when combined with radiotherapy. We have evaluated the impact of AZD2171 treatment on the efficacy of a clinically relevant fractionated radiotherapy schedule (2 Gy daily × 5) in Calu-6 (non-small-cell lung cancer) and Lovo (colorectal) human tumor xenograft models. Treatment with AZD2171 (6 mg/kg/day orally for 28 days) was initiated immediately after completion of the entire course of radiotherapy (sequential regimen) or 2 hours prior to each 2 Gy fraction of radiotherapy and continued post-radiotherapy (concomitant regimen). Mice bearing Calu-6 or Lovo xenografts, 250 mm3 in size, were randomized into treatment groups (Lovo n=5; Calu-6 n=7) immediately prior to treatment. The experimental endpoint was a quadrupling of tumor volume following the initiation of treatment (RTV4). Both Calu-6 and Lovo tumors showed an aggressive growth phenotype, with an RTV4 being achieved in an average of 12 days in vehicle-treated controls. AZD2171 or radiation alone yielded similar growth delays (RTV4treated-RTV4vehicle control) in both: 24±2 and 22±3 days, respectively in Calu-6 tumors and 23±3 and 19±2 days, respectively in Lovo tumors. Combining AZD2171 with radiotherapy yielded a significant improvement in radiation response in both models; tumor regression being induced by combined treatment (on days 12-13 in Lovo and days 16-17 in Calu-6 xenografts) in contrast to treatment with AZD2171 or radiation alone. Sequential and concomitant combination regimens resulted in similar growth delays in both Calu-6 (38±3 versus 36±3 days) and Lovo tumors (35±2 versus 32±1 days), indicating that there was no schedule dependency of the enhancement observed. Upon cessation of chronic AZD2171 treatment (post-irradiation), the growth rate mimicked that of vehicle-treated control tumors after a short delay. The dose-dependency of combining AZD2171 with radiation is being explored further with markers of tumor vascular integrity and perfusion. These data generated with AZD2171 further support inhibition of VEGF signaling as a means to enhance tumor radiation response in vivo.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]