Therapeutic Radiation in Genetically Engineered Mouse Models of Cancer

Abstract

Some drugs that target tumor metabolism are minimally effective in vitro but limit proliferation in vivo. Our goal was to develop a preclinical platform enabling us to test drugs that target cancer cell metabolism in combination with radiation therapy in vivo. Here we report the initial results of preclinical studies in autochthonous mouse models of prostate and colorectal cancer using radiation as monotherapy.A dose escalation study was performed in C57BL/6 wild-type mice using 1-5 fraction regimens with a BED of 90, 130, 180, and 250 (a/b = 3). Flank xenograft models of prostate cancer (22Rv1 and PC3 cells) were treated with 24 Gy in 4 fractions or sham irradiated (n = 10 animal per group, 40 animals total). Pb-Cre;Ptenfl/fl;p53fl/fl mice (autochthonous prostate cancer model) age 5 months were randomly assigned to two dose regimens (37.5 Gy in 5 fractions or 45 Gy in 5 fractions) or sham irradiation (n = 11-14 per group). Survival was estimated by Kaplan-Meier Analysis. Colorectal tumors were induced in male and female Villin-CreER;Apcfl/fl mice by intramucosal tamoxifen injection. Mice were assigned 2:1 to 37.5 Gy or sham irradiation (n = 10-15 per group). Treatment effect was measured as percent survival 6 months after tumor induction. In all cases pathologic response rate was determined using serial histologic sections and proliferation by Ki-67 immunohistochemistry.For a 2 cm field directed at the low abdomen and pelvis of mice, the maximum tolerated dose of radiation was 45 Gy delivered in 5 fractions. The intestinal tract was identified as the dose limiting organ for abdominopelvic radiation. In irradiated flank xenografts, growth delay was observed for all tumors compared with 100% progression in unirradiated controls. Pathologic complete response was observed in 1 of 10 (10%) 22Rv1 xenografts and 4 of 10 (40%) PC3 xenografts. In the autochthonous prostate cancer model, median survival was significantly improved in the 45 Gy (236 days, P < 0.0001) and 37.5 Gy (227 days, P = 0.0007) arms relative to control (206 days). Irradiated tumors were also smaller relative to control (mean difference -2.637 grams [95% CI -4.617 to -0.6563, P = 0.0153); however, all mice eventually died of local tumor progression. In the autochthonous colorectal cancer model, survival at 6 months was significantly improved in the radiation group relative to control (100% vs 40%, P = 0.0012). In both prostate and colorectal cancer autochthonous models the proliferation index at time of death (prostate) or 6 months after tumor induction (colorectal) was similar in irradiated and control cohorts.Hypofractionated radiation therapy can be safely administered to the abdominopelvic region in mice and improves survival in autochthonous mouse models of prostate and colorectal cancer. Radiation can induce pathologic complete responses in flank xenografts, but not autochthonous tumors, suggesting the presence of radioresistant persister cells in these models.