title: Multimodal imaging guided preclinical trials of vascular targeting in prostate cancer.
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.
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.|Current address: SUNY Upstate Medical University, Syracuse, NY, USA.
authors.forename: James
authors.initials: J
authors.lastname: Kalmuk
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Molecular and Cellular Biophysics and Biochemistry, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Folaron
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.|Current address: University at Buffalo - School of Medicine and Biomedical Sciences, Buffalo, NY, USA.
authors.forename: Julian
authors.initials: J
authors.lastname: Buchinger
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Pili
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Molecular and Cellular Biophysics and Biochemistry, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Mukund
authors.initials: M
authors.lastname: Seshadri
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D001578:Benzopyrans / Q000737:chemistry; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000737:chemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008870:Microtubules / Q000737:chemistry; D064847:Multimodal Imaging; D009389:Neovascularization, Pathologic; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging* / Q000473:pathology*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000098:blood supply / Q000000981:diagnostic imaging* / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction; D016896:Treatment Outcome; D014463:Ultrasonography
chemical_list: C000607144:AR protein, mouse; D000970:Antineoplastic Agents; D001578:Benzopyrans; D003287:Contrast Media; D011944:Receptors, Androgen; C000598757:crolibulin
keywords: androgen deprivation therapy; angiogenesis; multimodality imaging; prostate cancer; vascular disrupting agents