INTRODUCTION: Bone metastasis remains incurable with treatment restricted to palliative care. @entity14820 ( @entity8358 ) is targeted against multiple receptor @entity4149 kinases involved in @entity5 pathobiology, including hepatocyte growth factor receptor (MET) and @entity11132 ( @entity11132 ). @entity8358 has demonstrated clinical activity in advanced @entity263 with @entity75 visible on bone scans, implicating a potential role of the bone microenvironment as a mediator of @entity8358 effects. We characterised the effects of short-term administration of @entity8358 on bone in a range of in vivo models to determine how @entity8358 affects bone in the absence of @entity5 . METHODS: Studies were performed in a variety of in vivo models including male and female BALB/c @entity19 (age 6-17-weeks). Animals received @entity8358 (30mg/kg, 5* weekly) or sterile @entity4358 control for 5 or 10days. Effects on bone integrity ( CT), bone cell activity (PINP, TRAP ELISA), osteoblast and osteoclast number/mm trabecular bone surface, area of epiphyseal growth plate cartilage, megakaryocyte numbers and @entity236 were assessed. Effects of longer-term treatment (15-day _ 6-week administration) were assessed in male NOD/ @entity915 and beige @entity915 @entity19 . RESULTS: @entity8358 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 @entity1184 chondrocyte zone, was observed in all @entity8358 treated animals irrespective of administration schedule. Both male and female BALB/c @entity19 had increased megakaryocyte numbers/mm(2) tissue after 10-day @entity8358 treatment, in addition to @entity455 , reduced bone marrow cellularity and extravasation of red blood cells into the extra-vascular bone marrow. All @entity8358 -induced effects were transient and rapidly lost following cessation of treatment. CONCLUSION: Short-term administration of @entity8358 induces rapid, reversible effects on the bone microenvironment in vivo highlighting a potential role in mediating treatment responses.

Rapid modification of the bone microenvironment following short-term treatment with XXXX in vivo.

@entity11132 :: ('16542(Tax:10090)', 'Gene') :: ['VEGFR-2', 'vascular endothelial growth factor receptor 2'] @entity455 :: ('MESH:D014652', 'Disease') :: ['vascular ectasia'] @entity263 :: ('MESH:D011471', 'Disease') :: ['prostate cancer'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumour'] @entity75 :: ('MESH:D001927', 'Disease') :: ['resolution of lesions'] @entity19 :: ('10090', 'Species') :: ['mice', 'nude mice'] @entity4358 :: ('D014867', 'Chemical') :: ['H2O'] @entity1184 :: ('MESH:D006984', 'Disease') :: ['hypertrophic'] @entity14820 :: ('MESH:C558660', 'Chemical') :: ['Cabozantinib'] @entity915 :: ('MESH:D053632', 'Disease') :: ['SCID'] @entity8358 :: ('D002220', 'Chemical') :: ['CBZ'] @entity236 :: ('MESH:D001855', 'Disease') :: ['bone marrow composition'] @entity4149 :: ('D014443', 'Chemical') :: ['tyrosine']
@entity14820 :: (MESH:C558660,Chemical) :: ['Cabozantinib']
