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.
Highlights
Prostate cancer is the most common non-cutaneous malignancy and the second leading cause of cancer death in American males [1]
We first examined the vascular disruptive activity of EPC2407 against prostate cancer using a combination of non-invasive magnetic resonance imaging (MRI), immunohistochemistry (CD31), and histology (H&E)
Given the androgen-angiogenesis link in prostate cancer, we examined the vascular response of Myc-CaP tumors to castration using Contrastenhanced magnetic resonance imaging (CE-MRI) and contrast-enhanced ultrasound (CE-US) (Figure 3)
Summary
Prostate cancer is the most common non-cutaneous malignancy and the second leading cause of cancer death in American males [1]. Androgen withdrawal has been shown to inhibit tumor growth by reducing microvessel density and VEGF expression in castrationresistant prostate tumors [16] Consistent with these findings, selective obliteration of immature vessels, down regulation of VEGF mRNA expression and increased endothelial apoptosis have been reported in radical prostatectomy specimens obtained from patients subjected to androgen ablation [17]. These observations have provided the rationale for examining the potential of vascular targeted therapies against prostate cancer
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