Abstract 379: Monitoring adjuvant treatment effects of MMP 2/9 inhibition in experimental breast cancer bone metastases using VCT and ultra high-field MRI in a longitudinal study

Abstract

Abstract In the microenvironment of bone metastases, matrix metalloproteinases (MMPs) 2/9 are expressed by osteoblasts, osteoclasts and tumor cells, and in particular MMP 9 has been associated with osteoclast-mediated migration, invasion and angiogenesis. Using non-invasive imaging techniques including magnetic resonance imaging (MRI) and volumetric computed tomography (VCT) monitoring various aspects of treatment response including osteolysis, invasion and angiogenesis can be assessed longitudinally. The purpose of the study was to image effects of adjuvant MMP 2/9 inhibition in experimental breast cancer bone metastases using VCT and ultra high-field MRI. Human MDA-MB-231 breast cancer cells were inoculated into the femoral artery of nude rats, resulting in localized osteolytic bone metastases of the hind leg. Animals were either treated with a MMP 2/9 inhibitor (n=14) beginning immediately after tumor cell inoculation (p.i.) for 30 days (200 mg/kg orally) or sham-treated (n=17). Animals were imaged at days 10, 20 and 30 p.i. using VCT (Volume CT, Siemens) and MRI (7 Tesla, Siemens). Dynamic contrast-enhanced MRI (DCE-MRI) was performed to determine amplitude A (associated with blood volume) and exchange rate constant Kep (associated with perfusion and vessel permeability) in skeletal metastases. Volumetry of osteolysis and of the corresponding soft tissue tumor was obtained by VCT and MRI, respectively. All values were expressed as treatment over control ratios in percent (T/C%). Beginning from day 20 p.i., osteolyses and corresponding soft tissue tumors of bone metastases could be assessed by VCT and MRI at high isotropic resolution (200 µm for VCT, 110 µm for MRI). Strong uptake of contrast media within the soft tissue tumor enabled detailed assessment of volume and invasive behavior of the soft tissue tumor using ultra high-field MRI. Bone metastasis formation could not be prevented by MMP inhibition as the tumor take rate was not significantly different between the two groups within the observation time. However, the mean volumes of osteolysis and soft tissue tumor were significantly smaller upon MMP inhibition as compared to controls at days 20 (MRI, 28 T/C%; VCT, 46 T/C%) and 30 (MRI, 24 T/C%; VCT, 38 T/C%) p.i. As determined by DCE-MRI in skeletal metastases, a significant reduction of the amplitude A was assessed after MMP inhibition (day 30 p.i., 63 T/C%), whereas no significant differences for the exchange rate constant Kep were found between the groups. In conclusion, inhibition of MMPs 2/9 in experimental breast cancer bone metastases resulted in anti-resorptive, anti-invasive and anti-angiogenic effects as imaged longitudinally and at high resolution by VCT and ultra high-field MRI after adjuvant treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 379. doi:1538-7445.AM2012-379