Abstract 5307: VEGF downregulation by HSP90 inhibitor NVP-AUY922 visualized with89Zr-bevacizumab PET in triple negative breast cancer (TNBC)

Zirconium-89 (89Zr) labeled bevacizumab visualizes tumor vascular endothelial growth factor (VEGF) excretion in vivo, and can therefore serve as a potential biomarker for targeted drugs affecting VEGF levels. TNBC is more dependent upon alternative routes for their maintenance, such as angiogenesis, than hormone receptor or HER2 positive breast cancer. HSP90 inhibitors are known to impact the angiogenesis pathway via degradation of HSP90 client proteins such as HIF1α and VEGFRs, and in vitro studies have shown that breast cancer cells (including TNBC) are sensitive to these compounds. The aim of this study was to image modulation of VEGF expression in response to HSP90 inhibition with NVP-AUY922, a highly potent non-geldamycin HSP90 inhibitor, in a mouse model with a TNBC xenograft. Methods: Three groups of animals were used in this study, a control (n = 6), treated (n = 7) and placebo (n = 6) group. Twenty-two days after inoculation of TNBC cell line MDA MB-231, all mice received co-injection of 89Zr-bevacizumab and Indium-111 (111In) labeled IgG as aspecific control. VEGF-PET was performed 144 h after tracer injection. Ex vivo biodistribution studies were performed in the control group after the first scan week, for the treatment and placebo group after the second scan week, which was after 3 weeks of treatment. The control group received no treatment, the treatment and placebo group received respectively 50 mg/kg NVP-AUY922 or vehicle every-third-day (q3d) administrated intraperitoneally. Treatment effect was verified with histological response. Results: VEGF-PET showed a decreased 89Zr-bevacizumab tumor uptake of 44% (P = 0.0021) after 3 weeks NVP-AUY922 treatment compared to the baseline scan. Placebo treated mice showed no significant difference in bevacizumab uptake. These in vivo imaging data were supported by ex vivo biodistribution data. IgG tumor uptake was in all groups consistent, indicating that there was no influence on tumor perfusion due to the anti-angiogenic treatment. VEGF downregulation in the tumors was shown by immunohistochemistry of VEGF-A. Conclusion: NPV-AUY922 downregulates VEGF in a TNBC mouse model. VEGF-PET using 89Zr-bevacizumab can be used in vivo to monitor downregulation of VEGF excretion in response to HSP90 inhibition, and can therefore potentially serve as biomarker for early HSP90 inhibition effect in TNBC. Supported by a grant of the Dutch Cancer Society. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5307. doi:10.1158/1538-7445.AM2011-5307