Preclinical evaluation of KIT/PDGFRA and mTOR inhibitors in gastrointestinal stromal tumors using small animal FDG PET
J Exp Clin Cancer Res. 2010-12-01; 29(1):
DOI: 10.1186/1756-9966-29-173
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Pantaleo MA(1), Nicoletti G, Nanni C, Gnocchi C, Landuzzi L, Quarta C, Boschi S,
Nannini M, Di Battista M, Castellucci P, Fanti S, Lollini PL, Bellan E, Castelli
M, Rubello D, Biasco G.
Author information:
(1)Department of Hematology and Oncology Sciences L. A. Seragnoli, Sant’
Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
BACKGROUND: Primary and secondary drug resistance to imatinib and sunitinib in
patients with gastrointestinal stromal tumors (GISTs) has led to a pressing need
for new therapeutic strategies such as drug combinations. Most GISTs are caused
by mutations in the KIT receptor, leading to upregulated KIT tyrosine kinase
activity. Imatinib and nilotinib directly inhibit the kinase activity of KIT,
while RAD001 (everolimus) inhibits mTOR. We report a preclinical study on drug
combinations in a xenograft model of GIST in which effects on tumor dimensions
and metabolic activity were assessed by small animal PET imaging.
METHODS: Rag2-/-; γcommon -/- male mice were injected s.c. into the right leg
with GIST 882. The animals were randomized into 6 groups of 6 animals each for
different treatment regimens: No therapy (control), imatinib (150 mg/kg b.i.d.)
by oral gavage for 6 days, then once/day for another 7 days, everolimus (10
mg/kg/d.) by oral gavage, everolimus (10 mg/kg/d.) + imatinib (150 mg/kg b.i.d.)
by oral gavage for 6 days, then once/day for another 7 days, nilotinib (75
mg/kg/d.) by oral gavage, nilotinib (75 mg/kg/d.) + imatinib (150 mg/kg b.i.d) by
oral gavage for 6 days, then once/day for another 7 days. Tumor growth control
was evaluated by measuring tumor volume (cm3). Small animal PET (GE Explore
tomography) was used to evaluate tumor metabolism and performed in one animal per
group at base-line then after 4 and 13 days of treatment.
RESULTS: After a median latency time of 31 days, tumors grew in all animals
(volume 0,06-0,15 cm3) and the treatments began at day 38 after cell injection.
Tumor volume control (cm3) after 13 days of treatment was > 0.5 for imatinib
alone and nilotinib alone, and < 0.5 for the 2 combinations of drugs and for
everolimus alone. The baseline FDG uptake was positive in all animals.
FDG/SUV/TBR was strongly reduced over time by everolimus both as a single agent
and in combination with imatinib respectively: 3.1 vs. 2.3 vs. 1.9 and 2.5 vs 2.3
vs 0.
CONCLUSIONS: As single agents, all drugs showed an anti-tumor effect in GIST
xenografts but everolimus was superior. The everolimus plus imatinib combination
appeared to be the most active regimen both in terms of inhibiting tumor growth
and tumor metabolism. The integration of everolimus in GIST treatment merits
further investigation.