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Experimental and Molecular Therapeutics

Abstract 711: VEGF121/rGel inhibits prostate cancer-induced osteoblastogenesis by targeting osteoblasts and tumor neovasculature

Khalid A. Mohamedali, Zhi Gang Li, Michael W. Starbuck, Xinhai Wan, Jun Yang, Sehoon Kim, Wendy Zhang, Nora M. Navone and Michael G. Rosenblum
Khalid A. Mohamedali
1UT M.D. Anderson Cancer Ctr., Houston, TX.
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Zhi Gang Li
1UT M.D. Anderson Cancer Ctr., Houston, TX.
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Michael W. Starbuck
1UT M.D. Anderson Cancer Ctr., Houston, TX.
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Xinhai Wan
1UT M.D. Anderson Cancer Ctr., Houston, TX.
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Jun Yang
1UT M.D. Anderson Cancer Ctr., Houston, TX.
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Sehoon Kim
1UT M.D. Anderson Cancer Ctr., Houston, TX.
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Wendy Zhang
1UT M.D. Anderson Cancer Ctr., Houston, TX.
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Nora M. Navone
1UT M.D. Anderson Cancer Ctr., Houston, TX.
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Michael G. Rosenblum
1UT M.D. Anderson Cancer Ctr., Houston, TX.
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DOI: 10.1158/1538-7445.AM10-711 Published April 2010
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Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC

Abstract

Prostate cancer metastasis to bone usually produces bone-forming lesions although an osteolytic component is present in most cases. We have previously shown excellent efficacy against prostate cancer growth in bone in an osteolytic model (PC-3) with VEGF121/rGel, a chimeric fusion toxin of VEGF121 and the plant toxin gelonin (rGel) that targets VEGFR-1 and VEGFR-2. In the current study, we demonstrate that VEGF121/rGel systemic administration is also effective in a model of prostate cancer that displays the bone-forming phenotype when growing in the femurs of immunodeficient mice. Both murine osteoblast precursor (MC3T3) cells and primary mouse osteoblasts (PMOs) were shown to express VEGFR-1 but not VEGFR-2. VEGFR-1 mRNA expression was shown to down-regulate during osteoblast (MC3T3) differentiation. In vitro, treatment with VEGF121/rGel showed cytotoxicity against osteoblast precursor cells (IC50 = 15 nM) that was substantially reduced (IC50 > 1000 nM) after MC3T3 had been allowed to undergo differentiation. This suggests that the effect of VEGF121/rGel is specifically mediated by VEGFR-1. Furthermore, immunofluorescence microscopy showed that internalization of VEGF121/rGel into PMOs is VEGF121-receptor driven. In an ex vivo model of osteoblastic disease, 100 nM VEGF121/rGel significantly inhibited prostate cancer-mediated new bone formation in neonatal mouse calvaria. In vivo, systemic (iv, tail vein) administration of VEGF121/rGel significantly inhibited growth of the osteoblastic prostate cancer cell line MDA PCa 118b growing intrafemorally. Only 25% of VEGF121/rGel-treated mice showed the development of osteoblastic lesions compared to 90% of saline-treated mice. Micro-CT (µCT) analysis of isolated femurs demonstrated that intrafemoral growth of MDA PCa118b tumors caused a dramatic increase in bone volume and that treatment with VEGF121/rGel restored the bone volume fraction to normalized levels with no changes to the uninvolved contralateral femurs. H&E results confirmed that the osteoblastic growth of 118b cells was severely impeded. Our results clearly demonstrate that VEGF121/rGel administration may suppress the eventual development of skeletal prostate tumors and may have significant therapeutic effect against prostate cancer-mediated osteoblastic lesions in bone. Research conducted, in part, by the Clayton Foundation for Research.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 711.

  • ©2010 American Association for Cancer Research
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Cancer Research: 70 (8 Supplement)
April 2010
Volume 70, Issue 8 Supplement
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Abstract 711: VEGF121/rGel inhibits prostate cancer-induced osteoblastogenesis by targeting osteoblasts and tumor neovasculature
Khalid A. Mohamedali, Zhi Gang Li, Michael W. Starbuck, Xinhai Wan, Jun Yang, Sehoon Kim, Wendy Zhang, Nora M. Navone and Michael G. Rosenblum
Cancer Res April 15 2010 (70) (8 Supplement) 711; DOI: 10.1158/1538-7445.AM10-711

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Abstract 711: VEGF121/rGel inhibits prostate cancer-induced osteoblastogenesis by targeting osteoblasts and tumor neovasculature
Khalid A. Mohamedali, Zhi Gang Li, Michael W. Starbuck, Xinhai Wan, Jun Yang, Sehoon Kim, Wendy Zhang, Nora M. Navone and Michael G. Rosenblum
Cancer Res April 15 2010 (70) (8 Supplement) 711; DOI: 10.1158/1538-7445.AM10-711
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