“Bone metastasis remains incurable with treatment restricted to palliative care. Cabozantinib (CBZ) is targeted against multiple receptor tyrosine kinases involved in tumour pathobiology, including hepatocyte growth factor receptor (MET) and vascular endothelial growth factor receptor 2 (VEGFR-2). CBZ has demonstrated clinical activity in advanced prostate cancer with resolution of lesions visible on bone scans, implicating a potential role of the bone microenvironment as a mediator of CBZ effects. We characterised the effects of short-term administration of CBZ on bone in a range of in vivo models to determine how CBZ affects bone in the absence of tumour.
Studies were performed in a variety of in vivo models including male and female BALB/c nude [mice without strong immmune systems] mice (age 6-17-weeks). Animals received CBZ (30mg/kg, 5× weekly) or sterile H2O control for 5 or 10days. Effects on bone integrity (μCT), bone cell activity (PINP, TRAP ELISA), osteoblast and osteoclast number/mm trabecular bone surface, area of epiphyseal growth plate cartilage, megakaryocyte numbers and bone marrow composition were assessed. Effects of longer-term treatment (15-day & 6-week administration) were assessed in male NOD/SCID and beige SCID mice.
CBZ treatment had significant effects on the bone microenvironment, including reduced osteoclast and increased osteoblast numbers compared to control. Trabecular bone structure was altered after 8 administrations. A significant elongation of the epiphyseal growth plate, in particular the hypertrophic chondrocyte zone, was observed in all CBZ treated animals irrespective of administration schedule{although epiphyseal growth plate elongation does not always lead to increased height}. Both male and female BALB/c nude mice had increased megakaryocyte numbers/mm(2) tissue after 10-day CBZ treatment, in addition to vascular ectasia, reduced bone marrow cellularity and extravasation{leakage} of red blood cells into the extra-vascular bone marrow. All CBZ-induced effects were transient and rapidly lost following cessation of treatment.
Short-term administration of CBZ induces rapid, reversible effects on the bone microenvironment in vivo highlighting a potential role in mediating treatment responses.”
The elongation of epiphyseal growth plate may or not be promising based on what’s causing it. It could be a result of inhibition of endochondral ossification. The leakage of red blood cells could also be promising.
Cbz results in bone loss but perhaps it can do so in such a way to permit neo-growth plate formation. In the Cbz group there was much more bone marrow than control.
“CBZ induces reversible alterations to the epiphyseal growth plate by disrupting chondrocyte differentiation.”
