Data from Inhibition of Prostate Cancer Osteoblastic Progression with VEGF<sub>121</sub>/rGel, a Single Agent Targeting Osteoblasts, Osteoclasts, and Tumor Neovasculature

Abstract

<div>Abstract<p><b>Purpose:</b> A hallmark of prostate cancer (PCa) progression is the development of osteoblastic bone metastases, which respond poorly to available therapies. We previously reported that VEGF<sub>121</sub>/rGel targets osteoclast precursors and tumor neovasculature. Here we tested the hypothesis that targeting nontumor cells expressing these receptors can inhibit tumor progression in a clinically relevant model of osteoblastic PCa.</p><p><b>Experimental Design:</b> Cells from MDA PCa 118b, a PCa xenograft obtained from a bone metastasis in a patient with castrate-resistant PCa, were injected into the femurs of mice. Osteoblastic progression was monitored following systemic administration of VEGF<sub>121</sub>/rGel.</p><p><b>Results:</b> VEGF<sub>121</sub>/rGel was cytotoxic <i>in vitro</i> to osteoblast precursor cells. This cytotoxicity was specific as VEGF<sub>121</sub>/rGel internalization into osteoblasts was VEGF<sub>121</sub> receptor driven. Furthermore, VEGF<sub>121</sub>/rGel significantly inhibited PCa-induced bone formation in a mouse calvaria culture assay. <i>In vivo</i>, VEGF<sub>121</sub>/rGel significantly inhibited the osteoblastic progression of PCa cells in the femurs of nude mice. Microcomputed tomographic analysis revealed that VEGF<sub>121</sub>/rGel restored the bone volume fraction of tumor-bearing femurs to values similar to those of the contralateral (non–tumor-bearing) femurs. VEGF<sub>121</sub>/rGel significantly reduced the number of tumor-associated osteoclasts but did not change the numbers of peritumoral osteoblasts. Importantly, VEGF<sub>121</sub>/rGel-treated mice had significantly less tumor burden than control mice. Our results thus indicate that VEGF<sub>121</sub>/rGel inhibits osteoblastic tumor progression by targeting angiogenesis, osteoclastogenesis, and bone formation.</p><p><b>Conclusions:</b> Targeting VEGF receptor (VEGFR)-1- or VEGFR-2–expressing cells is effective in controlling the osteoblastic progression of PCa in bone. These findings provide the basis for an effective multitargeted approach for metastatic PCa. <i>Clin Cancer Res; 17(8); 2328–38. ©2011 AACR</i>.</p></div>