Abstract 4066: Early assessment of the XL184 treatment by Diffusion-Weighted MRI in metastatic prostate cancer to the bone murine model

Abstract

Abstract Ninety percent of patients with advanced prostate cancer develop metastases to the bone1. At present, there is no definitive means for assessing response to therapy, with RECIST identifying tumors in the bone as “unmeasureable”. Cabozantinib (XL184) is an oral small molecular pan-tyrosine kinase inhibitor of primarily MET and vascular endothelial growth factor receptor 2 (VEGFR2). MET is known to play key roles in cellular proliferation, migration and invasion, which contribute to the survival and metastasis of cancer cells. XL184 is already in Phase 2 trials to evaluate the therapeutic benefit on castration-resistant prostate cancer metastatic to the bone. Diffusion-weighted MRI (DW-MRI) is highly sensitive to microscopic changes in tumor tissue. Our goal was to evaluate DW-MRI for detection and quantification of changes in tumor tissue following one-week XL184 treatment. MR experiments were performed on a 9.4T MRI. Human prostate cancer (PC3) cells were implanted by direct intra-tibial injection into male SCID mice, which serves as a model for prostate bone metastases2. Upon measuring tumor volume of ∼10mm3 on anatomical scans, mice were distributed into 2 groups: XL184 at 30 mg/kg (N=7) and vehicle (N=5). Treatments were delivered by oral gavage once a day for 7 days. DW-MRI was performed at days 0 (pre-treatment), 1, 4, 7, 11, 14 and twice a week after. Apparent diffusion coefficient (ADC) maps were calculated analytically from DW-MR images acquired at b-value 120 and 1200 s/mm2. End point of the study was when tumor volume reached 5x the initial measure. Unpaired Student t-test was performed to compare MRI metrics. XL184 treated mice had smaller tumor volume growth rate than control mice. Significant differences in tumor volume were not observed until 14 days post-treatment initiation (p<0.05). In contrast, significantly higher ADC values (p<0.0.5) for the treated group compared to control were observed at day 7. These results demonstrate the use of DW-MRI as a early biomarker of tumor response to XL184 in a metastatic prostate cancer tumor model. DW-MRI may serve as a surrogate endpoint for assessing patient response to treatment in clinical trials.