Renal Cancer Resistance to Antiangiogenic Therapy Is Delayed by Restoration of Angiostatic Signaling

Bhatt, Rupal; Wang, Xiaoen; Zhang, Liang; Collins, M. P.; Signoretti, Sabina; Alsop, David; Goldberg, S. N.; Atkins, Michael; Mier, James

View/Open

Renal cancer resistance to antiangiogenic therapy is delayed by restoration of angiostatic signaling.pdf (3.281Mb)

Access Status

Full text of the requested work is not available in DASH at this time ("restricted access"). For more information on restricted deposits, see our FAQ.

Author

Bhatt, Rupal HARVARD

Wang, Xiaoen HARVARD

Zhang, Liang HARVARD

Collins, M. P.

Signoretti, Sabina HARVARD

Alsop, David HARVARD

Goldberg, S. N.

Atkins, Michael HARVARD

Mier, James HARVARD

Published Version

https://doi.org/10.1158/1535-7163.mct-10-0477

Metadata

Show full item record

Citation

Bhatt, Rupal S., Xiaoen Wang, Liang Zhang, Michael P. Collins, Sabina Signoretti, David C. Alsop, S. Nahum Goldberg, Michael B. Atkins, and James W. Mier. “Renal Cancer Resistance to Antiangiogenic Therapy Is Delayed by Restoration of Angiostatic Signaling.” Molecular Cancer Therapeutics 9, no. 10 (October 2010): 2793–2802. https://doi.org/10.1158/1535-7163.MCT-10-0477.

Abstract

Treatment of metastatic renal cell cancer (RCC) with antiangiogenic agents that block vascular endothelial growth factor (VEGF) receptor 2 signaling produces tumor regression in a substantial fraction of patients; however resistance typically develops within 6–12 months. The purpose of this study was to identify molecular pathways involved in resistance.

Treatment of mice bearing either 786-0 or A498 human RCC xenografts with sorafenib or sunitinib produced tumor growth stabilization followed by regrowth despite continued drug administration analogous to the clinical experience. Tumors and plasma were harvested at day 3 of therapy and at the time of resistance to assess pathways that may be involved in resistance. Serial perfusion imaging, and plasma and tumor collections were obtained in mice treated with either placebo or sunitinib alone or in combination with intratumoral injections of the angiostatic chemokine CXCL9.

Sunitinib administration led to an early down-modulation of interferon gamma (IFNγ) levels as well as reduction of IFNγ receptor and downstream angiostatic chemokines CXCL9-11 within the tumor. Intratumoral injection of CXCL9 while producing minimal effects by itself, when combined with sunitinib resulted in delayed resistance in vivo accompanied by a prolonged reduction of microvascular density and tumor perfusion as measured by perfusion imaging relative to sunitinib alone.

These results provide evidence that resistance to VEGFR therapy is due at least in part to resumption of angiogenesis in association with reduction of IFNγ related angiostatic chemokines, and that this resistance can be delayed by concomitant administration of CXCL9.