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. 2015 Mar 3;112(11):E1288–E1296. doi: 10.1073/pnas.1411848112

Fig. 4.

Fig. 4.

Combination ABT-263 and AZD8055 induce tumor regressions in a GEMM of SCLC. (A) Schematic of GEMM experiment. Gray space in mouse drawing indicates lung; red circle indicates lung tumor. (B) SCLC GEMMs harboring radiographically measurable lung tumors were randomized to receive treatment for 21 d with 80 mg/kg/day ABT-263, 16 mg/kg/day AZD8055, combination ABT-263/AZD8055, or no treatment. Chest and upper abdomen were imaged by MRI on the day before starting treatment and on day 21 of treatment. For each animal, the largest single lung tumor that was histologically confirmed to be a high-grade neuroendocrine tumor was measured radiographically, and volume was computed. The percentage of tumor volume change for each animal is plotted as a single circle, with black bars indicating mean and SEM. Also included for comparison is the percentage of tumor volume change by MRI when equivalent GEMMs were treated with cisplatin (7 mg/kg IP on days 1 and 8) and etoposide (10 mg/kg on days 2 and 9). Notably, the follow-up imaging time point for the chemotherapy-treated animals was 28 d. Unpaired two-tailed t tests for statistical significance comparing tumor volume percentage change between pairs of datasets were performed. Untreated versus ABT-263/AZD8055: P = 0.0222. AZD8055 versus ABT-263/AZD8055: P = 0.00350. ABT-263 versus ABT-263/AZD8055: P = 0.0333. Cisplatin/etoposide versus ABT-263/AZD8055: 0.1589 (not significant). (C–J) Representative examples of MRI images (with tumors outlined in green) on day 1 and day 21 of a 21-d treatment period, with the treatment indicated. The asterisk in G and H indicates additional tumor in a separate lobe, which is not included in measurements. (Scale bar: 5.0 mm.) (K–N) A GEMM SCLC tumor was dissected from the lung and implanted s.c. into a NSG mouse. An established tumor in the NSG mouse was then divided and s.c. implanted directly into four nu/nu NSG mice. There was no in vitro intermediate. Once tumors were established, nu/nu mice were treated for 3 d with (K) vehicle for both drugs, (L) AZD8055 (16 mg/kg/qd), (M) ABT-263 (80 mg/kg/qd), (N) ABT-263 (80 mg/kg PO daily), and AZD8055 (16 mg/kg PO daily). Tumors were collected and fixed 3 h after the final treatment. Sections from tumor were stained to detect CC3, shown as brown stain. (Scale bar: 100 μm.)