Juan Gloria, Bush Tammy L, Ma Connie, Manoukian Raffi, Chung Grace, Hawkins Jennifer M, Zoog Stephen, Kendall Richard, Radinsky Robert, Loberg Robert, Friberg Greg, Payton Marc
Departments of Oncology Biomarkers and Early Development, Thousand Oaks 91320, CA, USA.
J Transl Med. 2014 Nov 4;12:307. doi: 10.1186/s12967-014-0307-x.
The Aurora family of serine-threonine kinases are essential regulators of cell division in mammalian cells. Aurora-A and -B expression and kinase activity is elevated in a variety of human cancers and is associated with high proliferation rates and poor prognosis. AMG 900 is a highly potent and selective pan-aurora kinase inhibitor that has entered clinical evaluation in adult patients with advanced cancers. In mice, oral administration of AMG 900 blocks the phosphorylation of histone H3 on serine-10 (p-Histone H3), a proximal substrate of aurora-B and inhibits the growth of multiple human tumor xenografts, including multidrug-resistant models.
In order to establish a preclinical pharmacokinetic-pharmacodynamic (PK-PD) relationship for AMG 900 that could be translated to the clinic, we used flow cytometry and laser scanning cytometry detection platforms to assess the effects on p-Histone H3 inhibition in terms of sensitivity, precision, and specificity, in human tumor xenografts in conjunction with mouse skin and bone marrow tissues. Mice with established COLO 205 tumors were administered AMG 900 at 3.75, 7.5, and 15 mg/kg and assessed after 3 hours.
Significant suppression of p-Histone H3 in mouse skin was only observed at 15 mg/kg (p <0.0001), whereas in mouse bone marrow and in tumor a dose-dependent inhibition was achieved at all three doses (p ≤ 0.00015). These studies demonstrate that AMG 900 inhibits p-Histone H3 in tumors and surrogate tissues (although tissues such as skin may be less sensitive for assessing PD effects). To further extend our work, we evaluated the feasibility of measuring p-Histone H3 using fine-needle aspirate (FNA) tumor xenograft biopsies. Treatment with AMG 900 significantly inhibited p-Histone H3 (>99% inhibition, p <0.0001) in COLO 205 tumors. Lastly, we illustrate this LSC-based approach can detect p-Histone H3 positive cells using mock FNAs from primary human breast tumor tissues.
Phosphorylation of histone H3 is a useful biomarker to determine the pharmacodynamics (PD) activity of AMG 900. FNA biopsies may be a viable approach for assessing AMG 900 PD effects in the clinic.
丝氨酸 - 苏氨酸激酶的Aurora家族是哺乳动物细胞中细胞分裂的重要调节因子。Aurora - A和 - B的表达及激酶活性在多种人类癌症中升高，且与高增殖率和不良预后相关。AMG 900是一种高效且选择性的泛Aurora激酶抑制剂，已在晚期癌症成年患者中进入临床评估阶段。在小鼠中，口服AMG 900可阻断组蛋白H3丝氨酸 - 10位点的磷酸化（p - 组蛋白H3），这是Aurora - B的近端底物，并抑制多种人类肿瘤异种移植模型的生长，包括多药耐药模型。
为建立可转化至临床的AMG 900临床前药代动力学 - 药效学（PK - PD）关系，我们使用流式细胞术和激光扫描细胞术检测平台，结合小鼠皮肤和骨髓组织，评估在人肿瘤异种移植模型中对p - 组蛋白H3抑制作用的敏感性、精密度和特异性。给已建立COLO 205肿瘤的小鼠分别给予3.75、7.5和15 mg/kg的AMG 900，并在3小时后进行评估。
仅在15 mg/kg剂量时观察到小鼠皮肤中p - 组蛋白H3受到显著抑制（p <0.0001），而在小鼠骨髓和肿瘤中，所有三个剂量均实现了剂量依赖性抑制（p≤0.00015）。这些研究表明，AMG 900可抑制肿瘤和替代组织中的p - 组蛋白H3（尽管皮肤等组织对评估PD效应可能不太敏感）。为进一步拓展我们的工作，我们评估了使用细针穿刺抽吸（FNA）肿瘤异种移植活检来测量p - 组蛋白H3的可行性。用AMG 900治疗可显著抑制COLO 205肿瘤中的p - 组蛋白H3（抑制率>99%，p <0.0001）。最后，我们证明这种基于激光扫描细胞术的方法可使用来自原发性人类乳腺肿瘤组织的模拟FNA检测p - 组蛋白H3阳性细胞。
组蛋白H3的磷酸化是确定AMG 900药效学（PD）活性的有用生物标志物。FNA活检可能是在临床中评估AMG 900 PD效应的可行方法。
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