Abstract 5595: Imaging biomarker development for treatment efficacy for prostate cancer to the bone.
Authors: George Joshua S. , Galban Craig J. , Brisset Jean-Christophe , Hoff Benjamin , Galban Stephanie , Rehemtulla Alnawaz , Ross Brian D. 
Published: August 2014

Abstract
Approximately 70% of patients with late stage cancers metastasize to the bone. RECIST identifies these tumors as “unmeasureable” for therapeutic response assessment. Cabozantinib (CABO), a tyrosine kinase inhibitor of MET and VEGFR2, has shown promise as an effective therapy for metastatic prostate cancer to the bone. Patients treated with CABO showed a reduction in [Tc99m]-bone scan signal suggesting tumor response to treatment. Nevertheless, a return in signal to pre-treatment levels was observed in these patients following therapy completion. It has yet to be determined if the response observed in bone scans results from tumor death, changes in bone metabolism or vascular alterations in the tumor-stromal microenvironment resulting in reduced transport of the imaging tracer. The study objective was to assess tumor and bone response to CABO in an animal model of bone metastasis using a quantitative multi-modal imaging approach.
Twenty-seven male SCID mice were implanted with PC3 cell line in the right tibia. PC3 cells were transfected with a plasmid expressing a bioluminescence imaging (BLI) reporter for measuring apoptosis. When tumor volumes reached 10mm3 by MRI, mice were distributed into 2 groups: CABO at 30 mg/kg (N=13) and vehicle (N=14). Treatments were delivered by oral gavage once a day for three weeks. Starting pre-treatment, MRI and BLI were acquired every third day and CT every week. Tumor and bone volumes were monitored by manually contouring volumes of interest (VOI) on anatomical MRI and CT images, respectively. The apparent diffusion coefficient (ADC), an indirect measure of tumor cellularity, was calculated from diffusion MRI.
Mice treated with CABO were found to have significantly higher ADC values and slower growth profile than controls (p&lt;0.05) suggesting a drop in tumor cellularity. Following one week of treatment, BLI signal increased 7 fold over baseline values indicating a delay in tumor apoptosis. In contrast, ADC values and apoptosis activation were unchanged in the controls resulting in significant differences between groups (p&lt;0.05). As determined by CT, control mice had significantly more loss in bone volume than what was observed in the CABO treated mice, with differences first observed at day 14 post-treatment initiation (p&lt;0.05). CABO was found to activate cell death through apoptosis (BLI) resulting in reduced tumor cellularity (ADC) and inhibited tumor growth (anatomical MRI). Increased tumor burden may have reduced osteolytic processes causing less bone loss over controls. Quantitative diffusion MRI and CT, backed by preclinical optical techniques, provide highly sensitive temporal information on the tumor-stromal microenvironment and their interaction to a targeted therapeutic intervention. Translatable quantitative imaging techniques, i.e. MRI and CT, may provide individualized medicine to patients suffering from metastatic prostate cancer to the bone.
Citation Format: Joshua S. George, Craig J. Galban, Jean-Christophe Brisset, Benjamin Hoff, Stephanie Galban, Alnawaz Rehemtulla, Brian D. Ross. Imaging biomarker development for treatment efficacy for prostate cancer to the bone. [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 5595. doi:10.1158/1538-7445.AM2013-5595