Abstract P5-01-01: In Vivo Imaging of Modulation of IGF-1R Expression in a Mouse Model of Estrogen-Sensitive Breast Cancer

Abstract

Abstract Introduction: The insulin-like growth factor 1 receptor (IGF-1R) is a new target for the treatment of breast cancer. The expression of the IGF-1R may change during conventional breast cancer therapy. In vivo imaging of IGF-1R expression can be useful to select those patients who may benefit from IGF-1R targeted therapy. The aim of the study was to measure modulation of IGF-1R expression in estrogen receptor (ER) positive MCF-7 tumors with SPECT imaging. Material and methods: R1507, a monoclonal antibody directed against an the IGF-1R, was radiolabeled with Indium-111 (111In). In vitro, MCF-7 cells were cultured in the presence of 17β-estradiol or tamoxifen. Subsequently, cells were incubated with 111In-R1507 to evaluate up-or downregulation of IGF-1R expression. In vivo studies were performed in BALB/c nude mice with subcutaneous MCF-7 xenografts. Slow release 17β-estradiol pellets were implanted subcutaneously and mice were imaged 3 days after injection of 30 MBq 111In-R1507 with a U-SPECT-II camera. The concentration of 111In-R1507 in the tumor and normal tissues was determined ex vivo. In a second animal experiment, mice were treated with tamoxifen (50 mg/kg, 19 mg/kg, 6 mg/kg or vehicle) during 10 days. After seven days of treatment, mice received 111In-R1507 intravenously and the accumulation of the radiolabeled R1507 in the tumor and normal tissues was determined ex vivo. Results: Culturing the MCF-7 cells in the presence of 17β-estradiol for ≥ 16 hours resulted in an up-regulation of IGF-1R expression which plateaued after 48 hours (control versus 17β-estradiol: 0.03 versus 0.06 pmol/mg protein). Culturing the MCF-7 cells with 1 μM tamoxifen down-regulated IGF-1R expression from 0.035 to 0.019 pmol/mg protein. The ex vivo biodistribution study showed that tumor uptake of 111In-R1507 was significantly higher in the estradiol treated mice compared to non-treated mice (tumor uptake: 10.0 versus 7.7 %ID/g). Differences in tumor uptake were clearly visualized by SPECT imaging (Figure 1). Ex vivo biodistribution studies also revealed that the tumor-uptake of 111In-R1507 was lower in the tamoxifen treated mice compared to non-treated mice (tumor uptake: 20.5 versus 27.5 %ID/g). Discussion: 17β-estradiol resulted in up-regulation, whereas tamoxifen treatment resulted in down-regulation of IGF-1R expression of MCF-7 xenografts. Modulation of IGF-1R expression can be measured by SPECT imaging with 111In-R1507 as a tracer. Based on these preclinical data we postulate that this technique can be used to study the dynamics of IGF-1R expression during treatment of breast cancer patients and this may enable rational timing of anti-IGF-1R targeted therapy during treatment with conventional anti-cancer drugs. Fig 1. SPECT images of two mice with a subcutaneous MCF7 tumor (white arrows). In (A) the mouse has been treated with placebo and in (B) with estradiol. After treatment with estradiol a clear upregulation of IGF-1R is observed. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-01-01.