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

Abstract

Purpose: 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. Materials and 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 F116 ng/mL) were 2-fold higher than those in healthy volunteers (85 F 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 z40% in 8 patients, increased 2-to 5-fold in 8 patients, and remained essentially unchanged in 29 patients. Her-2 ECD concentrations decreased by z40% 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.

Plasma Insulin-Like Growth Factor-Binding Protein-2 Levels as Diagnostic and Prognostic Biomarker of Colorectal Cancer

“…Interestingly, the presence of loss of imprinting of IGF-II in patients with stage IV disease was associated with a significantly worse overall survival. Elevated serum IGFBP-2 levels have been reported in patients with malignancies of the ovary, colon, prostate, and advanced solid tumor (6,12,28,29). The result from our study was in agreement with previous studies that the plasma levels of IGFBP-2 are elevated in patients with CRC.…”

“…In clinical practice, because subjects with higher plasma IGFBP-2 levels are more likely to have CRC, they should undergo colonoscopic screening. However, we should keep in mind that higher IGFBP-2 levels are also present in several other cancers, such as ovarian cancer, prostate cancer, and advanced solid tumor (6,12,28,29). Several studies also demonstrated the crucial role of IGFBP-2 on the progression of cancer.…”

High IGFBP2 levels are not only associated with a better metabolic risk profile but also with increased mortality in elderly men

“…Further, it has been previously reported that IGFBP2 concentrations in the plasma of cancer patients are significantly higher than those in healthy volunteers (41). In our population, serum IGFBP2 was not related to prostate malignancy or any other form of malignancy at baseline.…”

Heat shock protein 90 inhibitors in the treatment of cancer: current status and future directions

“…This comes perhaps as no surprise since HSP90 inhibitors are known to be preferentially retained in tumor cells and not normal cells [89-91], and also there seems to be a fundamental difference between the HSP90 species in normal and tumor cells [90,91]. Perhaps for the same reasons, the clinical utility of other serum biomarkers such as soluble insulin growth factor binding protein and HER2 extracellular domain also remains to be validated [92]. …”