Multimodal imaging guided preclinical trials of vascular targeting in prostate cancer

// James Kalmuk 1, 4 , Margaret Folaron 1, 2 , Julian Buchinger 1, 5 , Roberto Pili 3 , Mukund Seshadri 1, 2 1 Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA 2 Department of Molecular and Cellular Biophysics and Biochemistry, Roswell Park Cancer Institute, Buffalo, NY, USA 3 Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA 4 Current address: SUNY Upstate Medical University, Syracuse, NY, USA 5 Current address: University at Buffalo – School of Medicine and Biomedical Sciences, Buffalo, NY, USA Correspondence to: Mukund Seshadri, e-mail: Mukund.Seshadri@roswellpark.org Keywords: multimodality imaging, vascular disrupting agents, angiogenesis, prostate cancer, androgen deprivation therapy Received: April 16, 2015 Accepted: June 19, 2015 Published: July 02, 2015 ABSTRACT The high mortality rate associated with castration-resistant prostate cancer (CRPC) underscores the need for improving therapeutic options for this patient population. The purpose of this study was to examine the potential of vascular targeting in prostate cancer. Experimental studies were carried out in subcutaneous and orthotopic Myc-CaP prostate tumors implanted into male FVB mice to examine the efficacy of a novel microtubule targeted vascular disrupting agent (VDA), EPC2407 (Crolibulin™). A non-invasive multimodality imaging approach based on magnetic resonance imaging (MRI), bioluminescence imaging (BLI), and ultrasound (US) was utilized to guide preclinical trial design and monitor tumor response to therapy. Imaging results were correlated with histopathologic assessment, tumor growth and survival analysis. Contrast-enhanced MRI revealed potent antivascular activity of EPC2407 against subcutaneous and orthotopic Myc-CaP tumors. Longitudinal BLI of Myc-CaP tumors expressing luciferase under the androgen response element (Myc-CaP/ARE-luc) revealed changes in AR signaling and reduction in intratumoral delivery of luciferin substrate following castration suggestive of reduced blood flow. This reduction in blood flow was validated by US and MRI. Combination treatment resulted in sustained vascular suppression, inhibition of tumor regrowth and conferred a survival benefit in both models. These results demonstrate the therapeutic potential of vascular targeting in combination with androgen deprivation against prostate cancer.