title: Preclinical evaluation of KIT/PDGFRA and mTOR inhibitors in gastrointestinal stromal tumors using small animal FDG PET.
abstract: 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.
authors.affiliation: Department of Hematology and Oncology Sciences L. A. Seragnoli, Sant' Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy. maria.pantaleo@unibo.it
authors.forename: Maria Abbondanza
authors.initials: MA
authors.lastname: Pantaleo
authors.forename: Giordano
authors.initials: G
authors.lastname: Nicoletti
authors.forename: Cristina
authors.initials: C
authors.lastname: Nanni
authors.forename: Chiara
authors.initials: C
authors.lastname: Gnocchi
authors.forename: Lorena
authors.initials: L
authors.lastname: Landuzzi
authors.forename: Carmelo
authors.initials: C
authors.lastname: Quarta
authors.forename: Stefano
authors.initials: S
authors.lastname: Boschi
authors.forename: Margherita
authors.initials: M
authors.lastname: Nannini
authors.forename: Monica
authors.initials: M
authors.lastname: Di Battista
authors.forename: Paolo
authors.initials: P
authors.lastname: Castellucci
authors.forename: Stefano
authors.initials: S
authors.lastname: Fanti
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Lollini
authors.forename: Elena
authors.initials: E
authors.lastname: Bellan
authors.forename: Mauro
authors.initials: M
authors.lastname: Castelli
authors.forename: Domenico
authors.initials: D
authors.lastname: Rubello
authors.forename: Guido
authors.initials: G
authors.lastname: Biasco
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001549:Benzamides; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000068338:Everolimus; D019788:Fluorodeoxyglucose F18; D046152:Gastrointestinal Stromal Tumors / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010879:Piperazines / Q000008:administration & dosage; D049268:Positron-Emission Tomography; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors* / Q000187:drug effects; D011743:Pyrimidines / Q000008:administration & dosage; D019275:Radiopharmaceuticals; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors* / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D000068877:Imatinib Mesylate; D000068338:Everolimus; C546843:mTOR protein, mouse; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; D058570:TOR Serine-Threonine Kinases; C498826:nilotinib; D020123:Sirolimus