Multimodal imaging provides insight into targeted therapy response in metastatic prostate cancer to the bone.

ABSTRACT

Metastatic prostate cancer to bone remains incurable, driving efforts to develop individualized, targeted therapies to improve clinical outcomes while limiting adverse side-effects. Due to the complexity in cellular signaling pathways and the interaction between cancer and its microenvironment, multiparametric imaging approaches for treatment response may improve understanding of the biological effects of therapy. An orthotopic model of castration resistant prostate cancer (CRPC) bone metastasis was treated with the tyrosine kinase inhibitor Cabozantinib (CABO). Response was assessed using CT to monitor bone volumes, 99mTc-MDP SPECT for bone metabolism, and anatomical and diffusion MRI for tumor volume and cell death. A concurrent clinical trial of CABO for CRPC patients also evaluated multimodality imaging in correlation with standard response criteria. Response in the preclinical study found significant slowing in tumor growth rate (P<0.01), rise in tumor apparent diffusion coefficient (ADC, P<0.001), and drop in 99mTc-MDP adsorption (P<0.05). Loss of bone volume did not slow with treatment, attributed to the highly aggressive and osteolytic nature of the PC3 cell line. Clinical trial analysis found only a single subject who progressed after 12 weeks of therapy. Imaging at 6 weeks corroborated the 12-week radiological assessment with positive response visible as increased ADC and decreased vascular metrics. Conversely, the subject who progressed at 12 weeks had no change in ADC, and substantial drops in vascular metrics. These results showcase a multifaceted translational imaging approach for detecting targeted treatment response with effective blockade of tumor vascularization, tumor cell kill, and reduced proliferation.