Dataset Information

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

ABSTRACT:

Introduction

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 (?CT), 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.

Conclusion

Short-term administration of CBZ induces rapid, reversible effects on the bone microenvironment in vivo highlighting a potential role in mediating treatment responses.

SUBMITTER: Haider MT

PROVIDER: S-EPMC4768060 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Publications

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

Haider Marie-Therese MT Hunter Keith D KD Robinson Simon P SP Graham Timothy J TJ Corey Eva E Dear T Neil TN Hughes Russell R Brown Nicola J NJ Holen Ingunn I

Bone 20150814

<h4>Introduction</h4>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 m ...[more]

PMID: 26279137

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Dataset Information

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

Introduction

Methods

Results

Conclusion

Publications

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

Similar Datasets

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