title: Targeting heat shock protein 90 for the treatment of malignant pheochromocytoma.
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.
authors: Program 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
authors: Alessio
authors: A
authors: Giubellino
authors: Carole
authors: C
authors: Sourbier
authors: Min-Jung
authors: MJ
authors: Lee
authors: Brad
authors: B
authors: Scroggins
authors: Petra
authors: P
authors: Bullova
authors: Michael
authors: M
authors: Landau
authors: Weiwen
authors: W
authors: Ying
authors: Len
authors: L
authors: Neckers
authors: Jane B
authors: JB
authors: Trepel
authors: Karel
authors: K
authors: Pacak
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000473:pathology; D010673:Pheochromocytoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C533237:STA 9090; D014230:Triazoles; C112765:tanespimycin