Machanismen der Radiosensitivierung von Tumorzellen bei Inhibition des EGF-Rezeptors

西妥昔单抗抑制表皮生长因子受体(EGFR)已成功应用于临床，提高头颈部鳞状细胞癌(HNSCC)的放射治疗效率。然而，并不是所有的患者都会真正从这种方法中受益。在第一个授权期内获得的自己的数据也证明了这一点。西妥昔单抗有效的放射增敏作用仅在所研究的少数细胞系中观察到，无论是细胞培养还是异种移植。同样，仅在HNSCC细胞系的特定亚群中观察到EGFR的表达与细胞放射敏感性之间存在明显的相关性。因此，有必要揭示EGFR(1)调节细胞放射敏感性的具体机制，并确定西妥昔单抗在哪些参数下实际上将导致有效的放射增敏(2)。在第一个授权期内，我们能够解开一些关于辐射后EGFR依赖的信号级联、DNA双链断裂(DSB)以及细胞周期调控之间相互作用的一些基本细节。基于这些数据，我们的目标是建立生物标记物，这将允许识别实际上可以用西妥昔单抗放射敏感性的肿瘤。鉴于放射治疗的实际相关性，我们还将研究西妥昔单抗联合顺铂放化疗的效果(3)，以及它对HPV感染的HNSCC肿瘤细胞的影响(4)。根据这些发现，应开发新的个体化抗EGFR治疗模式，以改善HNSCC患者的治疗。主要问题总结：1)EGFR通过什么机制调节细胞的放射敏感性？2)哪些机制预测西妥昔单抗的放射增敏？3)西妥昔单抗与顺铂的联合作用？4)HPV感染是否通过抑制EGFR而影响HNSCC细胞的放射增敏？

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?