Abstract 3924: Multimodality imaging investigation of response to cabozantinib in a VCaP model of prostate bone metastasis.
Authors: Graham Timothy J. , Box Gary , Attard Gerhardt , de Bono Johann S. , Eccles Suzanne A. , Davis Faith E. , Robinson Simon P. 
Published: August 2014

Abstract
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), a biomarker of tissue cellularity, was calculated for each tumour. From baseline, ADC significantly increased after 10 (p=0.024) and 15 (p=0.010) days of treatment, from 492 ± 16 to 556 ± 19 and 644 ± 44 (x10−6 mm2/s) respectively. There was no change in the ADC of the vehicle treated group, suggesting an early increase in tumour ADC may constitute a specific and clinically translatable biomarker of response in this model.
Excised tibias underwent an 18μm resolution μCT scan. Both osteosclerotic and osteolytic activity could be identified in tumour bearing tibias, which had 93% more bone volume (BV) compared to the contralateral control tibia. Cabozantinib had no significant effect on gross BV. When trabecular bone was quantified separately, tumour bearing tibias from treated mice showed a 95% increase in BV ratio (p=0.001). Moreover, there was significantly less tumour-related bone growth outside the bone marrow cavity in treated mice (p=0.048).
Citation Format: Timothy J. Graham, Gary Box, Gerhardt Attard, Johann S. de Bono, Suzanne A. Eccles, Faith E. Davis, Simon P. Robinson. Multimodality imaging investigation of response to cabozantinib in a VCaP model of prostate bone metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3924. doi:10.1158/1538-7445.AM2013-3924