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Molecular Imaging of the Efficacy of Heat Shock Protein 90 Inhibitors in Living Subjects

Departments of ¹ Radiology and ² Bioengineering, ³ Division of Nuclear Medicine, ⁴ Molecular Imaging Program at Stanford, and ⁵ Bio-X Program, Stanford University School of Medicine, Stanford, California and ⁶ Department of Medicine and Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York

Requests for reprints: Sanjiv Sam Gambhir, Stanford University School of Medicine, Departments of Radiology and Bioengineering, Bio-X Program, The James H. Clark Center, 318 Campus Drive, Clark E150, Stanford, CA 94305-5427. Phone: 650-725-2309; Fax: 650-897-9988; E-mail: sgambhir{at}stanford.edu.

Heat shock protein 90 (Hsp90)/p23 and Hsp90β/p23 interactions are crucial for proper folding of proteins involved in cancer and neurodegenerative diseases. Small molecule Hsp90 inhibitors block Hsp90/p23 and Hsp90β/p23 interactions in part by preventing ATP binding to Hsp90. The importance of isoform-selective Hsp90/p23 and Hsp90β/p23 interactions in determining the sensitivity to Hsp90 was examined using 293T human kidney cancer cells stably expressing split Renilla luciferase (RL) reporters. Interactions between Hsp90/p23 and Hsp90β/p23 in the split RL reporters led to complementation of RL activity, which was determined by bioluminescence imaging of intact cells in cell culture and living mice using a cooled charge-coupled device camera. The three geldanamycin-based and seven purine-scaffold Hsp90 inhibitors led to different levels of inhibition of complemented RL activities (10–70%). However, there was no isoform selectivity to both classes of Hsp90 inhibitors in cell culture conditions. The most potent Hsp90 inhibitor, PU-H71, however, led to a 60% and 30% decrease in RL activity (14 hr) in 293T xenografts expressing Hsp90/p23 and Hsp90β/p23 split reporters respectively, relative to carrier control–treated mice. Molecular imaging of isoform-specific Hsp90/p23 and Hsp90β/p23 interactions and efficacy of different classes of Hsp90 inhibitors in living subjects have been achieved with a novel genetically encoded reporter gene strategy that should help in accelerating development of potent and isoform-selective Hsp90 inhibitors. [Cancer Res 2008;68(1):216–26]

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