E-3810 Is a Potent Dual Inhibitor of VEGFR and FGFR that Exerts Antitumor Activity in Multiple Preclinical Models

Tumor growth inhibition after treatment with E-3810. The antitumor activity of E-3810 was tested in HT-29 colon cancer (A), in A2780 tumor xenograft (B), in RXF393 (C), in A498 (D), and in SKN12I (E) renal xenografts. All tumors were transplanted subcutaneously and when the masses reached 100 to 150 mg, mice were randomized to receive daily for 30 consecutive days vehicle (♦), E-3810 10 mg/kg (▴), 15 mg/kg (+), 20 mg/kg (▪), 30 mg/kg (Δ), 40 mg/kg (−), and sunitinib 40 mg/kg (◊). Panel D reports the relative tumor weight (RTW).

Antitumor activity of E-3810 in mice bearing A498 tumor xenograft. A, A498 tumors were allowed to grow to 400 mg. Mice were randomized to receive: vehicle (♦), E-3810 20 mg/kg every day for 30 days (▪), brivanib 100 mg/kg every day for 30 days (□), and sunitinib 40 mg/kg every day for 30 days (◊). *, P < 0.01; **, P < 0.05; ***, P < 0.005. B, A498 tumor cells were orthotopically transplanted in the kidney of nude mice. After 17 days, mice were randomized to receive vehicle (▴) or E-3810 (•) 20 mg/kg every day for 30 days. At the end of the treatment mice were killed and kidneys were harvested and weighed. C, mice transplanted with A498 tumors were randomized when the tumor reached 100 to 150 mg to receive vehicle (♦), E-3810 20 mg/kg every day for 30 days, (▪), or E-3810 20 mg/kg every day for 15 days x2 after a 1-week rest (x). D, mice transplanted with A498 tumors were randomized when the tumors reached 100 to 150 mg to receive vehicle (♦), sunitinib 40 mg/kg every day for 15 days × 2 cycles after a 1-week rest (•), and sunitinib 40 mg/kg every day for 15 days followed by E-3810 20 mg/kg every day for 15 days after a 1-week rest (○). *, P < 0.01, **, P < 0.05, and ***, P < 0.005.

Effects of E-3810 on tumor perfusion evaluated by DCE-MRI in A498 tumor bearing mice. A, illustrative MRI images. a, ROIs used for the image analysis; the red line outlines the whole tumor region, yellow and green areas represent respectively the tumor rim (a 1- to 1.5-mm-thick band in the tumor border) and core (center of the tumor). b and c, average images of the DCE series of 1 control and 1 treated animal, respectively. Images were taken at treatment time T2. B, box-plot of the IAUC₁₀ in tumor rim and core. IAUC₁₀ is the initial area under the signal enhancement curve calculated from the first 10 minutes of the DCE-MRI signal time course. The value of IAUC₁₀ is proportional to the amount of blood flow through the tumor during the first 10 minutes after contrast agent injection. Boxes refer to the control group (□) and E-3810 treated group (▪). *, P < 0.05 (Mann–Whitney U test); anomalous data points are plotted with a dot or a star.