Background: Cabozantinib (CBZ), a tyrosine kinase inhibitor targeted against MET and VEGFR2 has demonstrated positive effects in clinical trials of patients with bone metastasis. We hypothesised that treatment responses are partially mediated by cells of the bone microenvironment and report the first detailed characterisation of the bone microenvironment responses to CBZ treatment in vivo.
Methods: Nine-week old female GFP-Ob (BALB/cAnNCrl.Cg-Tg(Col1a1-GFP)Row Foxn1nu/nu) and 6-week old female BALB/c nude mice (n=4-5/group) received CBZ (30mg/kg, 200 μL) or H2O as control (200 μL) 5x weekly for 10 days (8 administrations in total). Bone structure (μCT), osteoblast and osteoclast activity (TRAP, PINP ELISA) and number/mm of trabecular bone, in addition to growth plate cartilage and bone marrow composition (histomorphometry) was determined.
Results: Bone structure was significantly altered in CBZ treated mice (GFP-Ob: Bone volume (BV/TV): CTRL: 13.48±0.54% vs. CBZ: 18.75±1.09%, p≤0.01; Trabecular number (Tb.N): CTRL: 2.65±0.13mm−1 vs. CBZ: 3.29±0.15mm-1, p≤0.05; Tb.Thickness (Tb.Th): CTRL: 0.0509±0.0012mm vs. CBZ: 0.0568±0.0009mm, p≤0.01; BALB/c nude: Tb.Th.: CTRL: 0.0360±0.0012mm vs. CBZ: 0.0431±0.0011mm, p≤0.01). This was accompanied by a reduction in osteoclast number (GFP-Ob: CTRL: 5.98±0.46 vs. CBZ: 4.15±0.30, p≤0.05; BALB/c nude: CTRL: 8.29±0.39 vs. CBZ: 6.78±0.47, p≤0.05). CBZ caused significant growth plate thickening (GFP-Ob: CTRL: 0.14±0.01mm2 vs. CBZ: 0.22±0.01mm2, p≤0.01; BALB/c nude: CTRL: 0.18±0.02mm2 vs. CBZ: 0.27±0.02mm2, p≤0.05). We also detected a CBZ-induced increase in megakaryocyte number (BALB/c nude: CTRL: 38.91±2.37 vs. CBZ: 47.30±1.77 p≤0.05) in addition to vascular ectasia, reduced bone marrow cellularity and extravasation of red blood cells into the bone marrow.
Conclusions: Our data suggest that CBZ may mediate therapeutic responses partially by modification of the bone microenvironment. (Covered by UK Home Office license PPL40/3531.)
Disclosure: The authors declared no competing interests. This work was supported by Breast Cancer Campaign UK (2010NovPhD17) and Exelixis.