title: Identification of new biomarkers for clinical trials of Hsp90 inhibitors.
abstract: The selective heat shock protein 90 (HSP90) inhibitor 17-allyamino-17-demethoxygeldanamycin (17-AAG) is currently in phase I/II clinical studies at numerous institutions. Heretofore, the biomarkers to detect 17-AAG bioactivity (Hsp70, Raf-1, and cyclin-dependent kinase 4) had to be analyzed by Western blot of cellular samples, either from tumor biopsies or peripheral blood leukocytes, a method that is both laborious and invasive. We have identified two new biomarkers [insulin-like growth factor binding protein-2 (IGFBP2) and HER-2 extracellular domain] that can be readily detected in patient sera by ELISA. Both secreted proteins are derived from or regulated by Hsp90 client proteins, raising hopes that they might be sensitive serum markers of HSP90 inhibitor activity. Several structurally unrelated HSP90 inhibitors dose-dependently decreased secretion of both IGFBP-2 and HER-2 extracellular domain into culture medium, and both proteins were more sensitive to HSP90 inhibitors than previously identified biomarkers. In sera from BT474 tumor-bearing mice, both IGFBP-2 and HER-2 extracellular domain were down-regulated by 17-AAG in a time-dependent and dose-dependent manner, coincident with the degradation of HER-2 and attenuation of AKT activity in the tumors. Furthermore, IGFBP-2 levels at the end of treatment correlated with residual tumor load, suggesting that IGFBP-2 might serve as an early indicator of therapeutic response. In addition, we also found that both IGFBP-2 and HER-2 extracellular domain levels are elevated in patient sera from several cancer types, suggesting that these novel secreted biomarkers could be valuable pharmacodynamic tools in clinical trials of HSP90 inhibitors.
authors.affiliation: Conforma Therapeutics Corp., 9393 Towne Center Drive, Suite 240, San Diego, CA 92121, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Daun
authors.initials: D
authors.lastname: Chung
authors.forename: Yong-Ching
authors.initials: YC
authors.lastname: Yang
authors.forename: Laura
authors.initials: L
authors.lastname: Neely
authors.forename: Steven
authors.initials: S
authors.lastname: Tsurumoto
authors.forename: Junhua
authors.initials: J
authors.lastname: Fan
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Marco
authors.initials: M
authors.lastname: Biamonte
authors.forename: John
authors.initials: J
authors.lastname: Brekken
authors.forename: Karen
authors.initials: K
authors.lastname: Lundgren
authors.forename: Francis
authors.initials: F
authors.lastname: Burrows
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016227:Benzoquinones; D014408:Biomarkers, Tumor / Q000737:chemistry / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D017321:Clinical Trials, Phase I as Topic; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D066298:In Vitro Techniques; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D047029:Lactams, Macrocyclic; D051379:Mice; D008819:Mice, Nude; D017434:Protein Structure, Tertiary / Q000187:drug effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D014408:Biomarkers, Tumor; D018841:HSP90 Heat-Shock Proteins; D018971:Insulin-Like Growth Factor Binding Protein 2; D047029:Lactams, Macrocyclic; D018719:Erb-b2 Receptor Tyrosine Kinases; D017828:Rifabutin; C112765:tanespimycin