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Updated: May 13, 2026
Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors
Published on: January 20, 2023
Targeting heat shock protein 90 for the treatment of malignant pheochromocytoma
Alessio Giubellino1, Carole Sourbier, Min-Jung Lee
1Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, Maryland, United States of America. giubella@mail.nih.gov
Abstract:
Metastatic pheochromocytoma represents one of the major clinical challenges in the field of neuroendocrine oncology. Recent molecular characterization of pheochromocytoma suggests new treatment options with targeted therapies. In this study we investigated the 90 kDa heat shock protein (Hsp90) as a potential therapeutic target for advanced pheochromocytoma. Both the first generation, natural product Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin), and the second-generation synthetic Hsp90 inhibitor STA-9090 (ganetespib) demonstrated potent inhibition of proliferation and migration of pheochromocytoma cell lines and induced degradation of key Hsp90 clients. Furthermore, ganetespib induced dose-dependent cytotoxicity in primary pheochromocytoma cells. Using metastatic models of pheochromocytoma, we demonstrate the efficacy of 17-AAG and ganetespib in reducing metastatic burden and increasing survival. Levels of Hsp70 in plasma from the xenograft studies served as a proximal biomarker of drug treatment. Our study suggests that targeting Hsp90 may benefit patients with advanced pheochromocytoma.
Insights
Targeting heat shock protein 90 (Hsp90) with inhibitors like ganetespib shows promise for treating advanced pheochromocytoma. These drugs reduced tumor growth and improved survival in preclinical models.
Area of Science:
- Neuroendocrine Oncology
- Molecular Oncology
- Pharmacology
Background:
- Metastatic pheochromocytoma is a significant challenge in neuroendocrine oncology.
- Recent advances in molecular characterization offer new therapeutic avenues.
- Heat shock protein 90 (Hsp90) is explored as a potential therapeutic target.
Purpose of the Study:
- To investigate Hsp90 as a therapeutic target for advanced pheochromocytoma.
- To evaluate the efficacy of Hsp90 inhibitors, 17-allylamino-17-demethoxygeldanamycin (17-AAG) and STA-9090 (ganetespib).
Main Methods:
- Assessed proliferation and migration of pheochromocytoma cell lines using Hsp90 inhibitors.
- Evaluated ganetespib's cytotoxicity in primary pheochromocytoma cells.
- Utilized metastatic pheochromocytoma models to test drug efficacy.
- Measured plasma Hsp70 as a biomarker for drug treatment.
Main Results:
- Both 17-AAG and ganetespib inhibited pheochromocytoma cell proliferation and migration.
- Hsp90 inhibitors induced degradation of key Hsp90 client proteins.
- Ganetespib demonstrated dose-dependent cytotoxicity in primary cells.
- In vivo studies showed reduced metastatic burden and increased survival with 17-AAG and ganetespib.
- Plasma Hsp70 levels correlated with drug treatment.
Conclusions:
- Targeting Hsp90 with inhibitors like ganetespib is a promising strategy for advanced pheochromocytoma.
- Hsp90 inhibition effectively reduces tumor burden and improves survival in preclinical models.
- Plasma Hsp70 can serve as a biomarker for Hsp90-targeted therapy.
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