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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 | Publisher: | AMER ASSOC CANCER RESEARCH | Source: | 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. | Document URI: | http://hdl.handle.net/1942/10638 | ISSN: | 1078-0432 | e-ISSN: | 1557-3265 | DOI: | 10.1158/1078-0432.CCR-08-2588 | ISI #: | 000267080800021 | Category: | A1 | Type: | Journal Contribution | Validations: | ecoom 2010 |
Appears in Collections: | Research publications |
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