59; post-treatment lateral (D), coronal (E) and axial (F) SUV no uptake. * Nilotinib + imatinib: 2.76; 3.28; 2.83; The mouse in the

imatinib group that had the first baseline and the second PET scan after treatment died during the protocol and the third PET scan was performed in a second animal; this new animal was comparable to the first one for Selleckchem KU-60019 tumor growth. Everolimus strongly reduced FDG uptake both alone and in combination with imatinib. Discussion Despite the dramatic results in disease control by TKIs in GIST, patients may develop primary and secondary drug resistance and this has led to a pressing need to develop new drugs or new strategies such as drug combinations. We have developed a xenograft model of GIST suitable for the preclinical study of new treatments evaluating both tumor size and function. This experiment used the model to study the antitumor activity of drug combinations, TKIs and m-TOR inhibitors [23]. We studied the activity of everolimus as a new single agent and two combinations of agents, imatinib associated with nilotinib and imatinib associated with everolimus. Imatinib and nilotinib as single agents were also evaluated for comparison and a non-treated group of animals served as a general control. As single agents

all 3 drugs controlled tumor growth. Everolimus alone was superior to nilotinib and imatinib (tumor BAY 63-2521 clinical trial volume (cm3) after 13 days of treatment: 0.4 vs 0.6 vs 0.6 respectively). Both combined regimens were more effective than single drugs (both 0.3 cm3 vs > 0.4 cm3). Considering tumor glucose metabolism, the control group showed a reduction of FDG SUV value due to the progressive development of necrosis due to a massive increase in tumor size. The imatinib group cannot be considered because the mouse subjected to the first 2 PET scans died before the third scan. All the other therapeutic regimens showed a reduction of FDG SUV value after treatment

administration, except the nilotinib and imatinib combination where the FDG SUV value remained stable. Attention should be paid to the everolimus and imatinib combination where FDG uptake was progressively reduced until there was no uptake after 13 days (SUV 2.59; 2.23; 0) (Figure 3). Everolimus showed the most interesting results Atorvastatin in our experiment as it had an antitumor effect both as a single agent and in combination with imatinib, considering both tumor volume control and inhibition of glucose metabolism. FDG was strongly reduced by everolimus alone and combined with imatinib. Everolimus inhibits mTOR which is a KIT/LY294002 price PDGFRA downstream pathway-dependent target and seems to be a promising agent in GIST. Other preclinical data on everolimus in a GIST cell line were reported by Chang et al with the evaluation of treatment response in the GIST 882 cell line by the reduction of phospho-AKT and phospho-S6 after imatinib and everolimus [26].