Mammalian target of rapamycin inhibitors as possible adjuvant therapy for microscopic residual disease in head and neck squamous cell cancer
Mammalian target of rapamycin inhibitors as possible adjuvant therapy for microscopic residual disease in head and neck squamous cell cancer
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DOI：
10.1158/0008-5472.can-06-2449
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发表时间：
2007-03-01
期刊：
影响因子：
11.2
通讯作者：
Caldito, Gloria
中科院分区：
文献类型：
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作者：
Nathan, Cherie-Ann O.;Amirghahari, Nazanin;Caldito, Gloria
分子治疗学鉴定肿瘤中的畸变以选择受益于分子靶向治疗的患者。eIF 4 E在头颈部鳞状细胞癌（HNSCC）患者的组织学上“无肿瘤”的手术切缘中的过表达是复发的独立预测因子，并且通过Akt/哺乳动物雷帕霉素靶（mTOR）途径被功能性激活。虽然mTOR抑制剂是细胞生长抑制剂，最好用于联合治疗，但我们假设它们可以在微小残留病（MRD）的HNSCC模型中用作长期单一药物。CCI-779是一种mTOR抑制剂，可抑制10号染色体上缺失的磷酸酶和张力蛋白同源物（PTEN）异常HNSCC细胞系FaDu的生长，抑制4 E结合蛋白1的磷酸化，导致与eIF 4 E的结合增加，并抑制碱性成纤维细胞生长因子和血管内皮生长因子。荧光原位杂交检测到68%的患者肿瘤和35%的无肿瘤边缘的PTEN异常。CCI-779抑制裸鼠中已建立的肿瘤的生长。然而，在MRD模型中，对照组（4%）和治疗组（50%）之间的无瘤率存在显著差异，中位无瘤时间分别为7天和18天（P < 0.0001）。在那些形成肿瘤的动物中，CCI-779导致肿瘤体积显著减小。Kaplan-Meier曲线显示CCI-779显著增加生存率（P < 0.0001）。在外周血单核细胞中，mTOR通路被抑制，这是对治疗反应的潜在替代标志物。用荧光素酶稳定转染FaDu使我们能够在MRD模型中用生物发光成像监测CCI-779的作用。这些结果为使用CCI-779作为mTOR激活的残留细胞的单一药剂的靶向分子疗法的临床试验铺平了道路。
Molecular therapeutics identifies an aberration in tumors to select patients that benefit from molecular targeted therapy. Overexpression of eIF4E in histologically "tumor-free" surgical margins of head and neck squamous cell cancer (HNSCC) patients is an independent predictor of recurrence and is functionally activated through the Akt/mammalian target of rapamycin (mTOR) pathway. Although mTOR inhibitors are cytostatic agents, best used in combination therapy, we hypothesize that they can be used as long-term single agents in an HNSCC model of minimal residual disease (MRD). CCI-779, an mTOR inhibitor, arrested growth of a phosphatase and tensin homologue deleted on chromosome 10 (PTEN) abnormal HNSCC cell line FaDu, inhibiting phosphorylation of 4E-binding protein 1, resulting in increased association with eIF4E and inhibition of basic fibroblast growth factor and vascular endothelial growth factor. Fluorescence in situ hybridization detected PTEN abnormalities in 68% of patient tumors and 35% of tumor-free margins. CCI-779 inhibited growth of established tumors in nude mice. However, in the MRD model, there were significant differences in the tumor-free rate between the control (4%) and the treatment group (50%), and the median tumor-free time was 7 versus 18 days, respectively (P < 0.0001). In those animals that formed tumors, CCI-779 caused a significant decrease in the tumor volume. The Kaplan-Meier curve showed that CCI-779 significantly increased survival (P < 0.0001). The mTOR pathway was inhibited in peripheral blood mononuclear cells potential surrogate markers of response to therapy. Stable transfection of FaDu with luciferase allowed us to monitor the effects of CCI-779 with bioluminescence imaging in the MRD model. These results pave the way for a clinical trial using targeted molecular therapy with CCI-779 as a single agent for mTOR-activated residual cells.