In vivo validation of effects of combination therapies on subpopulation composition. In vivo validation of effects of combination therapies on subpopulation.

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In vivo validation of effects of combination therapies on subpopulation composition. In vivo validation of effects of combination therapies on subpopulation composition. A, a schematic of the in vivo competition assay. Eμ-Myc; p19Arf−/− lymphoma cells were retrovirally transduced with desired shRNA, and mixed populations of tumor cells were tail-vein injected into recipient mice. Combination treatments were given at presentation of palpable tumor. Tumor cells were collected and analyzed at relapse. B, representative fluorescence imaging of vehicle-treated mice with mixed populations of parental-, shChk2 (GFP-labeled)-, and shBok (Tomato-labeled)–infected tumor cells, showing intratumoral heterogeneity in vivo. C, representative in vivo competition assay flow cytometry analysis of relapsed tumors following in vivo treatment with the indicated combination therapies. D, an in vivo competition assay showing the enrichment or depletion of subpopulations of shRNA-infected tumor cells. Vin/SAHA and IRT/CBL treatment data for the combined shBok and shChk2 populations are shown in lymph node, thymus, and spleen. Drug combination predictably enriched/depleted subpopulations, in agreement with in vitro results (Fig. 2). Data shown are mean ± SEM of three independent experiments (with 4–5 mice per experiment). **, P < 0.01 (two-tailed Student t test). E, relative tumor-free survival for each combination treatment on mice transplanted with heterogeneous parental/shChk2/shBok tumors, with days normalized to the median tumor-free survival of treated mice with homogeneous parental tumors. Vin/SAHA improved relative tumor-free survival when compared with IRT/CBL. Data were compiled from four independent experiments. P value was calculated using a log-rank test. RI, Resistance Index. Boyang Zhao et al. Cancer Discovery 2014;4:166-174 ©2014 by American Association for Cancer Research