Cilengitide affects tumor compartment, vascularization and microenvironment in experimental bone metastases as shown by longitudinal super(18)F-FDG PET and gene expression analysis

Purpose: Aim of this study was to investigate the specific treatment effects of inhibiting alpha v beta 3/ alpha v beta 5 integrins by cilengitide in an animal model of breast cancer bone metastases using dynamic super(18)F-FDG PET and gene expression analysis. Methods: For this purpose, nude rats bearing bone metastases were treated with cilengitide, a small molecule inhibitor of alpha v beta 3 and alpha v beta 5 integrins, from day 30 to 55 after tumor cell inoculation of MDA-MB-231 breast cancer cells (25 mg/kg, 5 days per week; n = 8 rats) and compared to control rats (n = 8). Dynamic super(18)F-FDG PET data were assessed at days 30, 35 and 55 after tumor cell inoculation determining the vascular fraction VB and the metabolic variables k1-k4. At day 55, genome-wide mRNA expression analysis was performed to assess the treatment-specific expression changes from cilengitide-treated and control rats. Results: In a longitudinal super(18)F-FDG PET study, the vascular fraction VB was significantly decreased in bone metastases between days 30/35, 30/55 and 35/55, whereas the kinetic parameters k1 and k4 were significantly decreased between days 30/55 in skeletal lesions of treated animals. Gene expression analysis from bone metastases at day 55 revealed that tumor-produced integrins ( alpha v beta 5) as well as factors relevant for angiogenesis ( alpha v beta 3, VEGF, PDGF), bone resorption (PTHrP and RANKL), extracellular matrix remodeling (collagen, CD44) and bone marrow microenvironment (CXCR4) were significantly reduced upon therapy with cilengitide. Conclusions: Here, we provide evidence that cilengitide inhibits pivotal factors of all compartments of bone metastases including tumor cells, vasculature and bone microenvironment in vivo and by whole-genome transcriptome analysis.