High Efficacy of Panobinostat Towards Human Gastrointestinal Stromal Tumors in a Xenograft Mouse Model
High Efficacy of Panobinostat Towards Human Gastrointestinal Stromal Tumors in a Xenograft Mouse Model
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DOI：
10.1158/1078-0432.ccr-08-2588
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发表时间：
2009-06-15
影响因子：
11.5
通讯作者：
Schoeffski, Patrick
中科院分区：
文献类型：
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作者：
Floris, Giuseppe;Debiec-Rychter, Maria;Schoeffski, Patrick
目的：组蛋白脱乙酰酶抑制剂已成为有效的抗癌化合物。使用裸鼠异种移植模型，我们首次评估了携带不同致癌KIT突变的人胃肠道间质瘤（GIST）对帕比司他（LBH 589）的反应，帕比司他单独给药或与伊马替尼联合给药。我们移植了携带KIT外显子13突变的人GIST 882细胞系和两份来自伊马替尼治疗后放射学进展患者的活检标本，外显子9突变。我们的研究包括4组：A组（n = 9;对照组），B组（n = 10;帕比司他10 mg/kg，每日一次，腹膜内），C（n = 9;伊马替尼150 mg/kg biddine，p.o.）和D（n = 8;帕比司他-伊马替尼组合，与上述相同的剂量/时间表）。治疗持续12天。使用标准变量定期测量肿瘤大小。组织学评估是由H&E，和免疫化学与KIT，裂解半胱天冬酶-3，Ki-67，和组蛋白乙酰化staining.Results：总体而言，GIST异种移植反应迅速帕比司他所示的肿瘤消退，坏死，萎缩，纤维化，和/或粘液样变性，显着的细胞凋亡，细胞增殖的大幅下降。在所有处理组中，H3和H4乙酰化均较对照水平显著增加。帕比司他和伊马替尼的组合进一步增强了大多数的评估parameters.Conclusions：我们第一次显示潜在的治疗活性帕比司他在人体胃肠道间质瘤，在体内。我们的研究结果保证了进一步探索组蛋白去乙酰化酶抑制剂治疗晚期GIST。我们的研究也是第一个使用患者活检建立的人GIST小鼠异种移植物。
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.