Imaging Heat Shock Protein 90 (Hsp90) Activity in Hormone-Refractory Prostate Cancer

摘要

During the first year of the funding period, we have labeled 1, 3- propoyldiamine modified geldanamycin with both fluorescent core (FITC in this case) and radioisotopes. Unfortunately, in vitro cell experiments failed to disclose the ability of FITC-GM to monitor Hsp90 activity changes after heat stimulation in prostate cancer cell lines. Small molecular Hsp90 inhibitors, at least GM derivatives, showed reasonable tumor accumulation after being labeled with 64Cu. However, in vitro experiments revealed that the GM derivatives are insufficient to tell the changes of both Hsp90 level and activity after stimulation. It might be more appropriate to use GM imaging for tumor detection instead of Hsp90 activity monitoring. Therefore, we switched gears to monitor Hsp90 activity indirectly through imaging downstream client proteins including EGFR and HER2 expression by 64Cu labeled antibodies. Hsp90 activity can be evaluated indirectly by imaging one or several of its downstream client proteins. The quantitative PET imaging of EGFR expression with 64Cu-DOTA-cetuximab is successful for monitoring the early therapeutic response upon 17- AAG treatment in a human prostate cancer PC-3 tumor model. The quantification of EGFR degradation upon 17-AAG treatment using PET imaging is consistent with other in vitro and ex vivo measurements. This strategy may be applied to monitor the therapeutic response in EGER-positive cancer patients under 17-AAG treatment.