Establishment of an ex vivo precision-cut lung slice model for the evaluation of drug-radiation responses

我们的研究重点是肺癌，我们的主要目标是确定新的药物靶点，确定如何最好地将新的治疗方法与当前的肺癌护理标准结合起来，并优化包括放射治疗在内的联合治疗。在其发展过程中，肺癌获得了对肿瘤持续生长至关重要的激活突变。例如，在几个关键的癌基因（包括EGFR、KRAS、ALK、BRAF、PIK3CA和ERBB2）中已经描述了复发性突变。由于在正常组织中没有发现这些激活突变，我们目前正在筛选能够选择性杀死这些细胞而不影响正常细胞的新化合物组合。重要的是，肺癌也可以获得肿瘤抑制基因的功能缺失突变。因此，肿瘤细胞可以变得高度依赖代偿性信号通路，从而可能成为杀死肿瘤细胞的目标。相反，没有肿瘤抑制基因突变的非肿瘤细胞较少依赖这些代偿途径，因此相对不受途径抑制的影响。我们目前正在筛选可导致选择性杀死肺癌中常见的肿瘤抑制基因突变细胞的靶点和化合物（例如TP53， LKB1， ATM）。

Our research focuses on lung cancer where our primary aim is to identify new drug targets and to determine how best to integrate novel therapies with current standards of care in lung cancer, and to optimise combination treatments including radiation therapy.During its development, lung cancer acquires activating mutations that are critical for continued tumour growth. For example, recurrent mutations have been described in several key oncogenes (including EGFR, KRAS, ALK, BRAF, PIK3CA and ERBB2). Since these activating mutations are not found in normal tissues, we are currently screening for combinations of novel compounds that can selectively kill these cells while leaving normal cells unaffected.Importantly, lung cancer can also acquire loss of function mutations in tumour suppressor genes. As a consequence, tumour cells can become highly dependent on compensatory signalling pathways, which might then be targeted in order to kill the tumour cells. In contrast, non-tumour cells without the tumour suppressor gene mutation, are less dependent on these compensatory pathways and therefore are relatively unaffected by pathway inhibition. We are currently screening for targets and compounds that can lead to selective killing of cells with tumour suppressor gene mutations that are common in lung cancer (e.g. TP53, LKB1, ATM).