High efficacy of panobinostat towards human gastrointestinal stromal tumors in a xenograft mouse model.
OBJECTIVE
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.


METHODS
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.
Floris
Giuseppe
G
Department of General Medical Oncology, Laboratory of Experimental Oncology, University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium. giuseppe.floris@med.kuleuven.be
Debiec-Rychter
Maria
M
Sciot
Raf
R
Stefan
Cristiana
C
Fieuws
Steffen
S
Machiels
Kathleen
K
Atadja
Peter
P
Wozniak
Agnieszka
A
Faa
Gavino
G
Schöffski
Patrick
P
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005091:Exons / Q000235:genetics; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000627:therapeutic use*; D000068877:Imatinib Mesylate; D007211:Indoles; D051379:Mice; D000077767:Panobinostat; D010879:Piperazines / Q000627:therapeutic use; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D011743:Pyrimidines / Q000627:therapeutic use; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007211:Indoles; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D000077767:Panobinostat; D019009:Proto-Oncogene Proteins c-kit