Multimodality imaging investigation of response to cabozantinib in a VCaP model of prostate bone metastasis
i might start charging : )
Prostate cancer (PCa) growth is incurable once it has metastasized to the bone microenvironment (BM). The altered BM provides a permissive niche to support tumour growth, and therapeutic strategies that target tumour-bone interactions and/or restore bone homeostasis are being pursued. This demands preclinical models that faithfully replicate tumour-bone interactions, and non-invasive imaging methods to interrogate such orthotopic models in vivo, improving the accuracy of, and accelerating pre-clinical drug development. We have used a multi-modality imaging approach to assess the radiology and response of an orthotopic VCaP PCa bone metastasis model to the c-Met/VEGFR2 inhibitor cabozantinib.
Direct intratibial injection of 2x106 luc-VCaP cells into male castrate SCID mice resulted in tumour formation within 20 days. The resulting tumours deregulated normal bone function, exhibited a predominantly sclerotic phenotype and, importantly, retained a rearrangement of the ERG oncogene, the most common chromosomal abnormality found in human PCa (40-80% of cases). Mice bearing established intratibial VCaP prostate tumours were treated daily with 30mg/kg p.o. cabozantinib (n=7) or vehicle alone (n=7) for 15 days.
Semi-quantitative photon flux measures from BLI showed a 52% regression after 14 days of treatment (p=0.016). Tumour volume was quantified from T2-weighted MR images acquired from contiguous transverse 500μm slices across the leg, with an in-plane resolution of 156μm2, in which tumour hyperintensity was clearly identifiable. Mean tumour volume was significantly (p=0.038) smaller in the cabozantinib treated group after 15 days treatment (21.9 ± 5.1 mm3) compared to the vehicle cohort (104 ± 43 mm3). These data show that cabozantinib exhibits powerful anti-tumour activity in this clinically relevant model of PCa.
Diffusion weighted MR images were acquired using a 10 b-value EPI sequence, from which the apparent diffusion coefficient (ADC),