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Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/10638

Title: High Efficacy of Panobinostat Towards Human Gastrointestinal Stromal Tumors in a Xenograft Mouse Model
Authors: Floris, Giuseppe
Debiec-Rychter, Maria
Sciot, Raf
Stefan, Cristiana
Fieuws, Steffen
Machiels, Kathleen
Atadja, Peter
Wozniak, Agnieszka
Faa, Gavino
Schoeffski, Patrick
Issue Date: 2009
Citation: CLINICAL CANCER RESEARCH, 15(12). p. 4066-4076
Abstract: Purpose: Histone deacetylase inhibitors have emerged as potent anticancer compounds. Using a nude-mouse xenograft model, for the first time we evaluated the response of human gastrointestinal stromal tumors (GIST) carrying different oncogenic KIT mutations to panobinostat (LBH589), administered single or in combination with imatinib. Experimental Design: We grafted the human GIST882 cell line with KIT exon 13 mutation and two biopsies from patients radiologically progressing under imatinib showing KIT exon11 and KIT exon9 mutations, respectively. Our study included 4 groups: A (n = 9; control), B (n = 10; panobinostat 10 mg/kg daily, i.p.), C (n = 9; imatinib 150 mg/kg bidaily, p.o), and D (n = 8; combination panobinostat-imatinib, same dose/schedule as above). Treatment lasted 12 days. Tumor size was measured regularly using standard variables. Histopathological assessment was by H&E, and immunohistochemically with KIT, cleaved caspase-3, Ki-67, and histone acetylation staining. Results: Overall, GIST xenografts responded rapidly to panobinostat as indicated by tumor regression, necrosis, hemorrhages, fibrosis, and/or myxoid degeneration, remarkable apoptosis, and substantial decline of cell proliferation. H3 and H4 acetylation increased significantly from control level in all treated groups. The combination of panobinostat and imatinib further enhanced most of the assessed parameters. Conclusions: We show for the first time potential therapeutic activity of panobinostat in human GISTs, in vivo. Our results warrant further exploration of histone deacetylase inhibitors for the treatment of advanced GISTs. Our study is also the first one on human GIST mouse xenografts established using patient biopsies.
Notes: [Floris, Giuseppe; Stefan, Cristiana; Wozniak, Agnieszka; Schoeffski, Patrick] Catholic Univ Louvain, Dept Gen Med Oncol, Univ Hosp Gasthuisberg, B-3000 Louvain, Belgium. [Floris, Giuseppe; Stefan, Cristiana; Wozniak, Agnieszka; Schoeffski, Patrick] Univ Hosp Gasthuisberg, Expt Oncol Lab, B-3000 Louvain, Belgium. [Debiec-Rychter, Maria; Machiels, Kathleen] Univ Hosp Gasthuisberg, Dept Human Genet, B-3000 Louvain, Belgium. [Sciot, Raf] Univ Hosp Gasthuisberg, Dept Pathol, B-3000 Louvain, Belgium. [Fieuws, Steffen] Katholieke Univ Leuven, I BioStat, Leuven, Belgium. [Fieuws, Steffen] Univ Hasselt, Leuven, Belgium. [Atadja, Peter] Novartis Inst Biomed Res, Cambridge, MA USA. [Faa, Gavino] Univ Cagliari, Dept Pathol, Ist Anat Patol, Cagliari, Italy.
URI: http://hdl.handle.net/1942/10638
DOI: 10.1158/1078-0432.CCR-08-2588
ISI #: 000267080800021
ISSN: 1078-0432
Category: A1
Type: Journal Contribution
Validation: ecoom, 2010
Appears in Collections: Research publications

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