I. Medizinische Klinik, Diagnostische und Interventionelle Radiologie, II. Medizinische Klinik, Onkologisches Zentrum, Universitätsklinikum Hamburg-Eppendorf; Labor Lademannbogen, Hamburg, Germany.
Clin Cancer Res. 2012 Sep 1;18(17):4621-32. doi: 10.1158/1078-0432.CCR-11-2968. Epub 2012 Jul 2.
Aurora kinases play a crucial role in cell-cycle control. Uncontrolled expression of aurora kinases causes aneuploidy and tumor growth. As conservative treatment options for advanced gastroenteropancreatic neuroendocrine tumors (GEP-NET) are disappointing, aurora kinases may be an interesting target for novel therapeutic strategies.
Human GEP-NETs were tested for aurora kinase expression. The efficacy of the new aurora kinase inhibitor danusertib was evaluated in two human GEP-NET cell lines (BON1 and QGP) in vitro and in vivo.
The majority of ten insulinomas and all 33 nonfunctional pancreatic or midgut GEP-NETs expressed aurora A despite a mostly high degree of cell differentiation. Both human GEP-NET cell lines expressed aurora kinase A and B, and high Ser10 phosphorylation of histone H3 revealed increased aurora B activity. Remarkably, danusertib led to cell-cycle arrest and completely inhibited cell proliferation of the GEP-NET cells in vitro. Decreased phosphorylation of histone H3 indicated effective aurora B inhibition. In a subcutaneous murine xenograft model, danusertib significantly reduced tumor growth in vivo compared with controls or mice treated with streptozotocine/5-fluorouracil. As a consequence, decreased levels of tumor marker chromogranin A were found in mouse serum samples. In a newly developed orthotopic model for GEP-NET liver metastases by intrasplenic tumor cell transplantation, dynamic MRI proved significant growth inhibition of BON1- and QGP-derived liver metastases.
These results show that danusertib may impose a new therapeutic strategy for aurora kinase expressing metastasized GEP-NETs.
极光激酶在细胞周期调控中起着至关重要的作用。极光激酶的不受控制的表达会导致非整倍体和肿瘤生长。由于晚期胃肠胰神经内分泌肿瘤（GEP-NET）的保守治疗选择令人失望，极光激酶可能成为新的治疗策略的一个有趣的靶点。
检测了人类 GEP-NET 中极光激酶的表达。在体外和体内评估了新型极光激酶抑制剂丹那司他滨对两种人类 GEP-NET 细胞系（BON1 和 QGP）的疗效。
尽管大多数细胞分化程度较高，但十种胰岛素瘤中的大多数和所有 33 种无功能胰腺或中肠 GEP-NET 均表达了极光 A。两种人类 GEP-NET 细胞系均表达了极光激酶 A 和 B，高丝氨酸 10 磷酸化组蛋白 H3 表明极光 B 活性增加。值得注意的是，丹那司他滨导致 GEP-NET 细胞在体外的细胞周期停滞，并完全抑制了细胞增殖。组蛋白 H3 的磷酸化减少表明极光 B 抑制有效。在皮下鼠异种移植模型中，与对照组或用链脲佐菌素/5-氟尿嘧啶治疗的小鼠相比，丹那司他滨显著减少了体内肿瘤生长。因此，在小鼠血清样本中发现肿瘤标志物嗜铬粒蛋白 A 的水平降低。在通过脾内肿瘤细胞移植建立的新的 GEP-NET 肝转移的原位模型中，动态 MRI 证明 BON1 和 QGP 衍生的肝转移的生长抑制具有显著意义。
这些结果表明，丹那司他滨可能为表达转移的 GEP-NET 的极光激酶提供一种新的治疗策略。
