Early effects of imatinib mesylate on the expression of insulin‐like growth factor binding protein‐3 and positron emission tomography in patients with gastrointestinal stromal tumor

Abstract

BACKGROUND.Imatinib has demonstrated marked clinical efficacy against gastrointestinal stromal tumor (GIST). Microarray technology, real‐time polymerase chain reaction (PCR) validation, and fluorodeoxyglucose‐positron emission tomography (FDG‐PET) imaging were used to study the early molecular effects of imatinib antitumor activity in GIST.METHODS.After exposure of sensitive and resistant sarcoma cell lines to imatinib for 24 to 48 hours, the changes in gene expression were evaluated using a 1146 unique pathway array with Western blot validation. Real‐time PCR was used to confirm changes in gene expression in human GIST samples (preimatinib biopsy and postimatinib surgical specimen after 3–7 days of therapy). FDG‐PET was performed to correlate radiographic findings with the effects of imatinib on gene expression in GIST.RESULTS.In all, 55 genes demonstrated a ≥ 2‐fold change after imatinib treatment of the GIST882 cells. Among these genes there was up‐regulation of insulin‐like growth factor binding protein‐3 (IGFBP‐3), a protein that modulates proliferation and apoptosis. Western blot analysis confirmed the increase of IGFBP‐3 only in imatinib‐sensitive GIST882 cells. Up to a 7‐fold induction (49% mean increase; P = .08) of IGFBP‐3 mRNA was found in tumor samples from patients with low residual FDG uptake, whereas there was an up to 12‐fold reduction (−102% mean decrease; P = .03) in IGFBP‐3 in those patients with high residual FDG uptake after imatinib therapy.CONCLUSIONS.In the current study, imatinib appears to regulate numerous genes and specifically induces IGFBP‐3 in GIST cells and tumor samples. IGFBP‐3 levels also were found to be inversely correlated with residual FDG uptake in GIST patients early in imatinib therapy. These initial observations suggest that IGFBP‐3 is an important early marker of antitumor activity of imatinib in GIST. Cancer 2006. © 2006 American Cancer Society.

Consensus report on the radiological management of patients with gastrointestinal stromal tumours (GIST): recommendations of the German GIST Imaging Working Group

“…18 F]FDG-PET or [ 18 F]FDG-PET/CT is to assess an early response if necessary [1315,18] and as an additional method in the case of inconclusive results on CT or MRI [4,37] . Choi et al [11] reported that 20% of lesions did not show a significant glucose uptake on pretreatment […”

“…18 F]FDG is a potential alternative to CT and is particularly indicated in terms of ambiguous CT or MRI results [4,37] . Furthermore, [ 18 F]FDG-PET allows early response assessment [1315] (Fig.…”

“…Pseudoprogression can also be caused by the appearance of a pseudo-new lesion that becomes hypoattenuated due to myxoid degeneration after onset of targeted therapy (Fig. 6) [34,37] . In contrast, real disease progression can be reflected by true new lesions, increasing lesion size, increasing attenuation of the rim or the entire lesion as well as the appearance of a new nodule within a mass, which presents a hyperattenuated nodule within a hypoattenuated lesion (Fig.…”

“…At the same time, changes in lesion size as well as the appearance of new lesions should be critically evaluated with respect to a potential pseudoprogression. PET/CT should only be applied to evaluate inconclusive results obtained by morphological imaging [4,37] . After 3 months of therapy, the response assessment should be based on changes in lesion density, size and the appearance of new lesions.…”

“…After 3 months of therapy, the response assessment should be based on changes in lesion density, size and the appearance of new lesions. As mentioned above, [ 18 F]FDG-PET/CT should only be applied to evaluate inconclusive results [4,37] .…”