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


METHODS
Studies were performed in a variety of in vivo models including male and female BALB/c nude mice (age 6-17-weeks). Animals received CBZ (30 mg/kg, 5× weekly) or sterile H2O control for 5 or 10 days. 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.


RESULTS
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. 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 of red blood cells into the extra-vascular bone marrow. All CBZ-induced effects were transient and rapidly lost following cessation of treatment.


CONCLUSIONS
Short-term administration of CBZ induces rapid, reversible effects on the bone microenvironment in vivo highlighting a potential role in mediating treatment responses.
Department of Oncology, University of Sheffield, Sheffield, UK. Electronic address: mhaider1@sheffield.ac.uk.
Marie-Therese
MT
Haider
School of Clinical Dentistry, University of Sheffield, Sheffield, UK. Electronic address: k.hunter@sheffield.ac.uk.
Keith D
KD
Hunter
CR-UK Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research, Sutton, Surrey, UK. Electronic address: Simon.Robinson@icr.ac.uk.
Simon P
SP
Robinson
CR-UK Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research, Sutton, Surrey, UK. Electronic address: timothy.graham@icr.ac.uk.
Timothy J
TJ
Graham
Department of Urology, University of Washington Medical Center, Seattle, WA, USA. Electronic address: ecorey@uw.edu.
Eva
E
Corey
South Australian Health and Medical Research Institute, Adelaide, SA, Australia. Electronic address: neil.dear@sahmri.com.
T Neil
TN
Dear
Department of Oncology, University of Sheffield, Sheffield, UK. Electronic address: r.hughes@sheffield.ac.uk.
Russell
R
Hughes
Department of Oncology, University of Sheffield, Sheffield, UK. Electronic address: n.j.brown@sheffield.ac.uk.
Nicola J
NJ
Brown
Department of Oncology, University of Sheffield, Sheffield, UK. Electronic address: I.Holen@Sheffield.ac.uk.
Ingunn
I
Holen
D000813:Anilides / Q000008:administration & dosage*; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D001859:Bone Neoplasms / Q000188:drug therapy / Q000556:secondary; D016723:Bone Remodeling / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D060833:Cellular Microenvironment / Q000187:drug effects; D005260:Female; D006132:Growth Plate / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000187:drug effects / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors
D000813:Anilides; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C558660:cabozantinib; D020794:Receptor Protein-Tyrosine Kinases
Bone marrow; Bone microenvironment; Osteoblast; Osteoclast; Vasculature