P5-13-05: Non-Invasive In Vivo 1H Magnetic Resonance Spectroscopy (MRS) Monitoring of Breast Tumor Response to IGF1R Targeted Therapy.
Authors: D Sachdev, JE Lin, C Lunzer, M Marjanska, M Garwood, D Yee
Journal: Cancer Research (2011)

Abstract Drugs targeting IGF1R are in clinical trials for breast cancer therapy. To date no suitable biomarkers of response have been identified for this therapy. It is important to select patients with tumors sensitive to disruption of IGF1R signaling. In addition, predicting response in patients quickly following initial treatment would also assist in the development of these strategies. While expression of IGF1R must be a minimum requirement for enrolling patients in trials with IGF1R agents, the mere expression of IGF1R is not necessarily sufficient for IGF-driven biology. We have previously shown that monitoring levels of total choline-containing compounds (tCho) non-invasively in breast cancer patients with locally advanced breast cancer is a useful predictor of response to primary systemic therapy. The tCho measured in these studies included choline, phosphocholine (pCho) and glycerophosphocholine (GPC). In this study, we examined if changes in tCho could be used as a marker of response to anti-IGF1R therapy. We tested the effect of two antibodies against IGF1R on intratumoral tCho levels in vivo. Mice bearing MCF-7 xenografts were subjected to MR imaging (MRI) and spectroscopy (MRS) to measure baseline tCho levels. MRI was performed at 4.7 Tesla (200 mHz) with a transceive surface coil. Single-voxel 1H spectroscopy was performed using water suppression and TE-averaging. A fully relaxed, unsuppressed water spectrum from the same voxel was acquired and tCho signal was referenced against the tissue water signal and expressed as mmol/kg water. The next day, mice were treated with 500 μg of scFv-Fc or phosphate buffered saline, or 800 μg EM164 or isotype-matched control antibody. 24 hours post-treatment, tCho was measured. The percent change in tCho 24h after treatment (% tCho24) was determined using the formula 100[(tCho24-tCho0)/tCho0]. In 9 out 10 mice treated with scFv-Fc, % tCho24 ranged from −26 to −81% of baseline levels while in mice treated with PBS the change was from 0% to +46%. EM164 treatment also caused decrease in tCho levels in 3 out of 3 mice while the control antibody did not. tCho was also monitored for a period of 2 weeks during the course of treatment with EM164 or control antibody; EM164 caused a decrease in tCho with % tCho of −35% while the control antibody treated mice showed % tCho of +43% over the two-week treatment. To further delineate the precise choline species regulated by IGF signaling, MCF-7 cells were treated in vitro with IGF-I for 24h and cell extracts subjected to MRS at 14.1 Tesla using a NMR scanner. IGF-I enhanced levels of pCho compared to choline and GPC. We next investigated if there is a mechanistic link between IGF signaling and choline metabolism. MCF-7 cells were treated with IGF-I for 10 minutes or 24h and levels of choline kinase (ChoK), the rate-limiting enzyme that converts choline to pCho and then phosphatidylcholine were examined. Surprisingly, IGF-I signaling enhanced ChoK levels. Our data show that decrease in tCho could be a surrogate marker of early response to anti-IGF1R therapy. Thus, MRS to measure tCho levels could be included in the design of clinical trials with such reagents to quickly identify patients whose tumors are sensitive to inhibition of IGF1R. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-05.