Efficacy of the HSP90 inhibitor NVP-AUY922 correlates with decreased vessel permeability and reduced interstitial fluid pressure

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NVP-AUY922 is a novel synthetic Heat Shock Protein 90 (HSP90) ATPase inhibitor which has recently entered Phase I clinical trials for the treatment of solid tumors and hematological malignancies. HSP90 is an ubiquitously expressed molecular chaperone which plays an important role in the conformational maturation and activation of a large number of ‘client’ proteins that have been implicated in oncogenesis. HSP90 has attracted considerable interest as a therapeutic target for cancer treatment since HSP90 ATPase inhibition may induce the simultaneous degradation of multiple oncogenic proteins. As part of its preclincial evaluation, the antitumor activity of NVP-AUY922 was determined in the rat orthotopic syngeneic breast cancer model BN-472. The compound exhibits dose dependent efficacy when administered i.v. once per week. In addition, the pharmacokinetic profile of NVP-AUY922 demonstrates specific compound retention in tumor tissue and high liver and plasma clearance. HSP70 expression levels in the tumors were used as a pharmacodynamic marker and we found a good correlation between HSP70 induction and the pharmacokinetic profile of NVP-AUY922. To further understand the biological events responsible for the in vivo efficacy of NVP-AUY922 we investigated whether compound treatment would affect vessel permeability. Several proteins in the VEGF signaling pathway are HSP90 client proteins including VEGFR2, Src and PKB/Akt. We hypothesized that inhibition of HSP90 with NVP-AUY922 would mediate decreased vessel permeability as determined in a modified VEGF dependent Miles assay. Indeed, a significant, time and dose dependent increase in vessel permeability was observed in vivo. Decreased vessel permeability was found to correlate with reduced transient interstitial fluid pressure at efficacious dose levels. Overall, our data demonstrate that NVP-AUY922 is highly efficacious in the orthotopic BN-472 breast cancer model at exposures causing decreased vessel permeability and reduced interstitial fluid pressure in tumor tissue.