NVP-AUY922 is a synthetic inhibitor of Heat Shock Protein 90 (HSP90) ATPase activity. HSP90 is a ubiquitously expressed molecular chaperone which plays an important role in the conformational maturation and activation of a large number of \#8220;client\#8221; proteins that have been implicated in oncogenesis. HSP90 has attracted considerable interest as a therapeutic target for cancer treatment since HSP90 ATPase inhibition induces the simultaneous degradation of multiple oncogenic proteins. Antitumor activity and tolerability of NVP-AUY922 was determined in preclinical cancer animal models. The pharmacokinetic profile of NVP-AUY922 in plasma and tumor tissues was evaluated at well tolerated, efficacious dose levels. We observed tumor specific compound retention and rapid tissue and plasma clearance. Ex vivo PK/PD analyses of tumor tissues upon acute dose or after termination of in vivo efficacy studies showed a time-dependent association between compound concentration and down-regulation of target proteins. The receptor tyrosine kinase ErbB2 is a well described Hsp90 client protein which is often overexpressed in breast cancer. The combination of NVP-AUY922 and an ErbB2 inhibitor was evaluated in the ErbB2 overexpressing human breast cancer model BT-474. We demonstrate significantly better in vivo antitumor effect when trastuzumab is combined with the ErbB2 inhibitor trastuzumab compared to either inhibitor alone. Disruption of the HSP90 chaperone hetero-complex, resulting in a loss of Heat Shock Factor-1 (HSF-1) repression and induction of Heat Shock Protein 70 (HSP70) is considered to be one of the most robust biomarkers to detect inhibition of Hsp90 ATPase activity in clinical trials. In the current dose escalation study in patients with solid tumors, induction of HSP70 is being evaluated for pharmacodynamic effect of AUY922 treatment in a surrogate tissue, peripheral blood monocytes (PBMC), at multiple time-points. In order to determine whether Hsp70 can be used as a reliable biomarker in combination trials, we generated an A375 melanoma cell line expressing luciferase under the control of the human Hsp70 promoter (A375/Hsp70-luc). Using Xenogen imaging technology we were able to monitor the effect of various antitumor agents on Hsp70 induction. Among the compounds evaluated in this model only administration of Hsp90 inhibitors and to a lesser degree the HDAC inhibitor NVP-LBH589 resulted in Hsp70 induction. These data indicate that Hsp70 may be used as a reliable biomarker in clinical trials where Hsp90 inhibitors are combined with conventional anticancer agents.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5649.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009