Machanismen der Radiosensitivierung von Tumorzellen bei Inhibition des EGF-Rezeptors

通过抑制 EGF 受体实现肿瘤细胞放射增敏的机制

• 批准号: 38048311
• 负责人: Professor Dr. Ekkehard Dikomey
• 金额: --
• 依托单位: Labor für Strahlenbiologie und Experimentelle Radioonkologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2012-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/38048311?language=en
• 关键词: Machanismen; der; Radiosensitivierung; von; Tumorzellen

The inhibition of the epidermal growth factor receptor (EGFR) by the monoclonal antibody cetuximab is already successfully used in the clinics to increase the treatment efficiency of head and neck squamous cell carcinoma (HNSCC) by radiotherapy. However, not all patients will actually benefit from this approach. This is also demonstrated by own data achieved within the first grant period. Efficient radiosensitization by cetuximab was only observed in few of the cell lines investigated, both for cell cultures as well as xenografts. Likewise, a clear correlation between EGFR expression and cellular radiosensitivity was only observed for a specific subgroup of HNSCC cell lines. Therefore, it is necessary to unveil the specific mechanisms, by which the cellular radiosensitivity is modulated by EGFR (1) and also to identify the parameters under which cetuximab will actually result in efficient radiosensitization (2). Within the first grant period we were able to unravel some essential details about the interaction between EGFR dependent signalling cascades, DNA double strand break (DSB) as well as cell cycle regulation after irradiation. Based on these data we are aiming to establish biomarkers, which will allow to identify tumours that can actually be radiosensitized by cetuximab. Due to the actual relevance in radiotherapy we will also investigate the effect of cetuximab in combination with radio-chemotherapy using cisplatin (3) and, additionally, its effect in HPV infected HNSCC tumour cells (4). Based on these findings new models for individualized anti-EGFR therapy shall be developed to improve the therapy of HNSCC patients.Summary of the central questions:1) By what mechanisms does the EGFR regulate the cellular radiosensitivity?2) Which mechanisms predict the radiosensitization by cetuximab?3) What is the combined effect of cetuximab together with cisplatin?4) Does a HPV infection influence the radiosensitization of HNSCC cells by EGFR inhibition?

单克隆抗体西妥昔单抗（cetuximab）对表皮生长因子受体（epidermal growth factor receptor，EGFR）的抑制作用已成功应用于临床，提高头颈部鳞状细胞癌（head and neck squamous cell carcinoma，HNSCC）的放射治疗效率。然而，并非所有患者都能从这种方法中受益。第一个资助期内获得的数据也证明了这一点。西妥昔单抗的有效放射增敏作用仅在研究的少数细胞系中观察到，无论是细胞培养物还是异种移植物。同样，EGFR表达与细胞放射敏感性之间的明确相关性仅在HNSCC细胞系的特定亚组中观察到。因此，有必要揭示EGFR调节细胞放射敏感性的具体机制（1），并确定西妥昔单抗实际产生有效放射增敏作用的参数（2）。在第一个资助期内，我们能够解开一些关于EGFR依赖性信号级联，DNA双链断裂（DSB）以及辐射后细胞周期调控之间相互作用的基本细节。基于这些数据，我们的目标是建立生物标志物，这将允许识别实际上可以被西妥昔单抗放射增敏的肿瘤。由于在放疗中的实际相关性，我们还将研究西妥昔单抗与使用顺铂的放化疗组合的作用（3），以及其在HPV感染的HNSCC肿瘤细胞中的作用（4）。在此基础上，我们将开发新的个体化抗EGFR治疗模型，以提高HNSCC患者的治疗效果。中心问题概述：1）EGFR通过何种机制调节细胞的放射敏感性？2)西妥昔单抗的放射增敏机制是什么？3)西妥昔单抗联合顺铂的联合作用是什么？4)HPV感染是否通过抑制EGFR影响HNSCC细胞的放射增敏作用？