GSI and rapamycin treatment inhibits human T-ALL growth and extends survival. (A) GSI and rapamycin treatment inhibits human T-ALL growth in vitro. The human T-ALL cell line (TALL-1) was treated with 0, 0.5, 1, 5, 10, or 50 μM MRK-003 in addition to 0, 1, or 100 nM rapamycin and ATP activity quantified using the Vialight assay kit. (B) The combination treatment (GSI and rapamycin) inhibits human T-ALL growth in vivo more effectively than treatment with either single agent. CD1 nu/nu mice were injected with human T-ALL cell line, TALL-1. When tumors reached 250 mm3, xenograft mice were treated with vehicle, rapamycin, MRK-003, or a combination of MRK-003 and rapamycin for 3 weeks. MRK-003 was dosed at either 0 or 150 mg/kg by mouth once a week. Rapamycin was dosed at either 0 or 20 mg/kg by mouth daily. After treatment, tumors were callipered and body weight was recorded. Bar graph indicates relative tumor volumes at killing. The following statistics were analyzed by a t test; vehicle versus rapamycin (P = .001), vehicle versus MRK-003 (P = .325), rapamycin versus rapamycin + MRK-003 (P = .002), MRK-003 versus rapamycin + MRK-003 (P = .001). (C) GSI and rapamycin treatment inhibits human leukemic growth in vivo and increases overall survival. After 3 weeks of treatment with vehicle, MRK-003 (150 mg/kg per week), rapamycin (20 mg/kg daily), or MRK-003 and rapamycin, T-ALL-1 xenograft mice were monitored for tumor recurrence. Tumor-free survival was compiled on a Kaplan-Meier survival plot. Data were analyzed by a log rank test (P = .058).
