Abstract LB-458: Additive effects of caloric restriction and IGF-I receptor blockade on the progression of 22RV1 prostate cancer xenografts

Colette Galet; Ashley Gray; R. James Barnard; Brandon Castor; Junxiang Wan; Jonathan Said; Pedro Beltran; Franck Calzone; Pinchas Pinchas Cohen; William J. Aronson

doi:10.1158/1538-7445.AM2011-LB-458

INTRODUCTION: IGF-I receptor (IGF-1R) blockade has been shown to slow prostate cancer xenograft growth. Caloric restriction inhibits xenograft growth through modulation of the insulin-IGF axis. We hypothesized that caloric restriction combined with IGF-I receptor blockade would result in additive suppression of prostate cancer growth. METHODS: Sixty SCID mice were subcutaneously injected with 22RV1 cells (suppressible with IGF-1R blockade in vitro) and randomized to four groups: 1) ad libitum feeding with intraperitoneal saline (ad lib), 2) ad libitum with 20 mg/kg twice weekly intraperitoneal AMG479 IGF-I receptor blocking antibody (Amgen), (ad lib/Ab), 3) 40% calorie restriction with intraperitoneal saline (CR), 4) 40% calorie restriction with intraperitoneal AMG479, (CR/Ab). Diet and treatment with either antibody or saline were initiated one week after tumor injection. The animals were euthanized after 19 days of treatment and tumors were weighed. Fasting plasma levels of insulin, IGF-I, IGFBP-3, and IGFBP-1 were measured and tumors were stained for Ki67, TUNEL, and CD31. Cleaved caspase 3 and AKT activation in tumors were assessed by western blot. RESULTS: Mean tumor weight at sacrifice in the CR/Ab group was significantly lower (p<0.05) than the other three groups (166 mg ± 23 vs. Ad lib: 467 mg ± 58, Ad lib/Ab: 502 mg ± 52 and CR: 295 mg ± 56). Mean tumor weight was also lower in the CR group as compared to the ad lib groups (p< 0.05). Cleaved Caspase 3/Total Caspase 3 ratios were increased by 2 to 3 fold in the CR groups compared to the ad lib groups irrespectively of antibody therapy. Ki67 expression was significantly decreased in the CR/Ab group compared to the ad lib group (77 ± 1.2 vs. 81± 1.4 p<0.05). Plasma IGF-1 and IGFBP-3 levels were significantly reduced in the CR groups compared to the Ad lib groups irrespectively of treatment. AKT activation correlated to plasma IGF-1 levels. Mice in the Ad lib/Ab group had increased plasma insulin levels compared to the Ad lib group. The CR and CR/AB groups had significantly lower plasma insulin (80 and 60% reduction respectively) relative to the ad lib group. Angiogenesis was not affected by these interventions. CONCLUSION: Combining caloric restriction with antibody therapy targeting the IGF-1 receptor had additive anticancer effects on 22RV1 tumor growth. This additive anticancer effect may be due to suppression of the insulin elevation observed with AMG479 resulting in increased apoptosis and decreased proliferation in the CR/Ab combination arm. Further pre-clinical and clinical trials are warranted to evaluate the role of dietary interventions in combination with anti IGF1R antibody therapy. Citation Format: Authors. Abstract title [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-458. doi:10.1158/1538-7445.AM2011-LB-458

Abstract LB-458: Additive effects of caloric restriction and IGF-I receptor blockade on the progression of 22RV1 prostate cancer xenografts

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