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dc.contributor.authorBhatt, Rupal
dc.contributor.authorWang, Xiaoen
dc.contributor.authorZhang, Liang
dc.contributor.authorCollins, M. P.
dc.contributor.authorSignoretti, Sabina
dc.contributor.authorAlsop, David
dc.contributor.authorGoldberg, S. N.
dc.contributor.authorAtkins, Michael
dc.contributor.authorMier, James
dc.date.accessioned2021-08-30T14:55:09Z
dc.date.issued2010-08-10
dc.identifier.citationBhatt, 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.en_US
dc.identifier.issn1535-7163en_US
dc.identifier.issn1538-8514en_US
dc.identifier.urihttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37369185*
dc.description.abstractTreatment 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.en_US
dc.language.isoen_USen_US
dc.publisherAmerican Association for Cancer Research (AACR)en_US
dc.relation.isversionofdoi:10.1158/1535-7163.MCT-10-0477en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956167/en_US
dash.licenseMETA_ONLY
dc.titleRenal Cancer Resistance to Antiangiogenic Therapy Is Delayed by Restoration of Angiostatic Signalingen_US
dc.typeJournal Articleen_US
dc.description.versionAccepted Manuscripten_US
dc.relation.journalMolecular Cancer Therapeuticsen_US
dash.depositing.authorAlsop, David
dc.date.available2021-08-30T14:55:09Z
dc.identifier.doi10.1158/1535-7163.mct-10-0477
dc.source.journalMolecular Cancer Therapeutics
dash.source.volume9en_US
dash.source.page2793-2802en_US
dash.source.issue10en_US
dash.contributor.affiliatedZhang, Liang
dash.contributor.affiliatedAtkins, Michael
dash.contributor.affiliatedWang, Xiaoen
dash.contributor.affiliatedMier, James
dash.contributor.affiliatedSignoretti, Sabina
dash.contributor.affiliatedBhatt, Rupal
dash.contributor.affiliatedAlsop, David


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