Apoptotic and anti-vascular activity of imatinib in GIST patients

Abstract

9001 Imatinib mesylate (IM) is a potent inhibitor of the Kit/platelet-derived growth factor receptor(PDGFR) tyrosine kinases. We are investigating the early mechanisms of anti-tumor activity of IM in GIST patients(pts) as measured by 18-fluorodeoxyglucose(FDG) positron emission tomography(PET) imaging. We hypothesize that early reductions in GIST FDG avidity after IM therapy are due to induction of tumor cell apoptosis and anti-vascular activity. Pts with planned resection of their GIST were treated with IM(600 mg/day) preoperatively. Perfusion computed tomography(CT) and FDG PET scans were performed before and after IM therapy for 3, 5, or 7 days. All pts underwent pre-IM biopsy followed by resection no more than 6 hours after completion of IM therapy. CT perfusion parameters included blood flow(BF) and blood volume(BV) of the whole tumor. PET imaging was used to assess the maximum standardized uptake value(SUV) of FDG. Paired tumor biopsies and resected tumors were examined using immunofluorescent laser scanning cytometry to quantify endothelial and tumor cell apoptosis, microvessel density(MVD), phospho-Kit and phospho-PDGFR. 10 GIST pts underwent PET, 7 had a decrease in SUV of greater than 30% while 3 had no decrease or no baseline FDG avidity. The PET responders had a decrease while non-responders had an increase in BF (-37.8% vs. +38.5%, P=.02). PET responders had a decrease in BV compared to the increase seen in non-responders (-29.5% vs +24%, P=.04). 4 responders to IM had a decrease in phospho-Kit in the tumor-associated endothelium(avg. -45%, P=.07) and tumor cell compartment(avg -52%, P=.13). These tumors displayed a 7-fold (P=.08) and 2.8 fold (P=.23) increase in endothelial and tumor cell death, respectively, and a 36% reduction in MVD after IM. The tumor with reduction in BF(-74%) and BV(-61%) displayed the greatest increase in endothelial cell death(.05% to 11%, p<0.05). The most significant reduction in MVD(-78%, P<.05) was observed in the tumor with the greatest reduction in FDG uptake(-85%). IM induces tumor cell apoptosis after brief IM therapy and may have anti-vascular effects on GISTs. We believe that inhibition of Kit activation in the tumor-associated endothelium by IM is a novel finding. No significant financial relationships to disclose.