Evaluation of plasma insulin-like growth factor binding protein 2 and Her-2 extracellular domain as biomarkers for 17-allylamino-17-demethoxygeldanamycin treatment of adult patients with advanced solid tumors.
OBJECTIVE
Interaction of 17-allylamino-17-demethoxygeldanamycin (17-AAG) with heat shock protein 90 results in proteasomal degradation of many proteins, including Her-2-neu, with subsequent decreased expression of insulin-like growth factor binding protein-2 (IGFBP-2). Concentrations of both IGFBP-2 and Her-2 extracellular domain (Her-2 ECD) in sera of mice bearing BT474 human breast cancer xenografts decrease after 17-AAG treatment. We investigated whether this phenomenon occurred in patients.


METHODS
Eight to 15 plasma samples were obtained between 0 and 72 h from 27 patients treated with single-agent 17-AAG at doses between 10 and 307 mg/m(2) and 18 patients treated with 17-AAG at doses between 220 and 450 mg/m(2) combined with 70 to 75 mg/m(2) of docetaxel. Pretreatment plasma samples were also obtained from 12 healthy volunteers. Plasma IGFBP-2 and Her-2 ECD concentrations were quantitated by ELISA.


RESULTS
Pretreatment plasma IGFBP-2 concentrations in patients (171 +/- 116 ng/mL) were 2-fold higher than those in healthy volunteers (85 +/- 44 ng/mL; P < 0.05). Following 17-AAG treatment, there were no consistent dose-dependent or time-dependent changes in plasma IGFBP-2 and Her-2 ECD concentrations. IGFBP-2 concentrations decreased by >or=40% in 8 patients, increased 2- to 5-fold in 8 patients, and remained essentially unchanged in 29 patients. Her-2 ECD concentrations decreased by >or=40% in 10 patients, increased 1.5- to 5-fold in 2 patients, and remained essentially unchanged in 25 patients.


CONCLUSIONS
As previously reported, IGFBP-2 concentrations in plasma of cancer patients are significantly higher than those in healthy volunteers. In contrast to a mouse model, 17-AAG treatment was not consistently associated with decreases in IGFBP-2 or Her-2 ECD concentrations in patient plasma.
Eiseman
Julie L
JL
Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213-1863, USA. eisemanj@msx.upmc.edu
Guo
Jianxia
J
Ramanathan
Ramesh K
RK
Belani
Chandra P
CP
Solit
David B
DB
Scher
Howard I
HI
Ivy
S Percy
SP
Zuhowski
Eleanor G
EG
Egorin
Merrill J
MJ
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016227:Benzoquinones / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000097:blood* / Q000187:drug effects; D047029:Lactams, Macrocyclic / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000097:blood* / Q000187:drug effects; D043823:Taxoids / Q000627:therapeutic use
D000970:Antineoplastic Agents; D016227:Benzoquinones; D014408:Biomarkers, Tumor; D000077143:Docetaxel; D018971:Insulin-Like Growth Factor Binding Protein 2; D047029:Lactams, Macrocyclic; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; C112765:tanespimycin