Pharmacodynamic effects of PI3K inhibitor NVP-BKM120 on breast carcinomas in MMTV-CreBrca1f/fTrp53+/− mice. Pharmacodynamic effects of PI3K inhibitor NVP-BKM120.

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Pharmacodynamic effects of PI3K inhibitor NVP-BKM120 on breast carcinomas in MMTV-CreBrca1f/fTrp53+/− mice. Pharmacodynamic effects of PI3K inhibitor NVP-BKM120 on breast carcinomas in MMTV-CreBrca1f/fTrp53+/− mice. Female virgin mice developed spontaneous breast cancers at ages 8 to 12 months. A, representative 18FDG PET–CT scan images of a tumor-bearing mouse at baseline (image on the left) and within 48 hours after starting treatments with the PI3K inhibitor NVP-BKM120 (50 mg/kg/d by gavage, image on the right). This mouse had developed 4 simultaneous tumors. Arrows in orange, green, blue, and white are used to identify different tumors upon baseline (left) and posttreatment (right) imaging. The color palette for uptake ranges from dark blue to bright yellow with increasing count intensity. The changes in FDG uptake were determined as described in Methods. They decreased by 45% (tumor with orange arrow), 64% (green arrow), 64% (blue arrow), and 56% (white arrow). B, suppression of AKT phosphorylation on S473 as a result of treatments with NVP-BKM120 in vivo. Tumor tissue was obtained via core needle biopsy before and after 2 weeks of treatments with NVP-BKM120, fixed, and processed for IHC with anti-pAKT (S473) antibodies. For additional IHC images, see Supplementary Fig. S1. C, decrease in FDG uptake in 6 mammary carcinomas. Relative decrease in FDG uptake was determined by the ratio of uptake at 48 hours (blue bars) or 2 weeks (red bars) to baseline. Tumor-specific FDG uptake was determined as described in Methods. For additional PET–CT images, see Supplementary Fig. S2. D, concordance of decrease in FDG uptake and tumor shrinkage during a 2-week treatment with PI3K inhibitor NVP-BKM120. The tumor-bearing animal was imaged with FDG-PET (top, tumor indicated with a yellow arrow before and after treatment, decrease in uptake 93%) and concomitant CT scan (bottom) before (left) and on treatment (right). The tumor is again marked in the CT scan with a yellow arrow in the axial and sagittal plane. The red outline indicates the tumor circumference before treatment to visualize treatment effect on tumor size. Ashish Juvekar et al. Cancer Discovery 2012;2:1048-1063 ©2012 by American Association for Cancer Research