NFkB als therapeutisches Zielmolekül bei Glioblastomen

侵袭性脑肿瘤（如胶质母细胞瘤; GBM）的发病率相对较低，但仍然是癌症相关死亡的主要原因，因为目前这种实体的临床概念在很大程度上仍然是姑息性的。GBM含有对化疗或放疗具有高度抗性的干细胞样肿瘤细胞。此外，强侵袭性和快速肿瘤扩张是GBM的病理特征。肿瘤实质组分如控制治疗化合物对脑的生物利用度的血液肿瘤屏障代表了神经肿瘤护理的额外障碍。转录因子NFkB是控制肿瘤细胞的干细胞样性状、浸润性生长和肿瘤治疗后DNA损伤应答的诱导的信号传导中心。因此，NFkB代表了肿瘤疾病的极好治疗靶标。然而，以前在临床上解决NFkB信号传导的尝试产生了不可接受的副作用。 我们最近已经表明，药物大麻二酚（CBD;在儿科神经病学中作为Epidiolex应用）治疗性地调节NF κ B通路，从而对大范围的GBM具有有效的抗肿瘤作用。获得了CBD敏感性GBM的预测生物标志物，为转化研究提供了基础。在我们目前的项目中，我们正在对人类GBM活检进行前瞻性研究，以严格测试药理学测定中CBD敏感肿瘤的预测生物标志物和遗传标志物。此外，我们研究了它们的转录组学、蛋白质组学、基因组学和表观遗传学特征的体外和体内模型，以鉴定与CBD一起具有协同治疗作用并通过调节NF κ B信号传导发挥抗肿瘤作用的药理学化合物。该项目将提供新的治疗策略，以解决NFkB在肿瘤疾病中的广泛病理作用。

Aggressive brain tumors (like glioblastomas; GBM) have a relatively low incidence, but nevertheless represent a leading cause for cancer-related death since current clinical concepts for this entity remain largely palliative. GBM contain stem-like tumor cells that are highly resistant to chemo- or irradiation therapy. Furthermore, strong invasiveness and rapid tumor expansion are pathological hallmarks of GBM. Tumor parenchymal components like the blood tumor barrier, which controls bioavailability of therapeutic compounds to the brain, represent an additional obstacle for neuro-oncological care. The transcription factor NFkB is a signaling hub controlling stem-like traits of tumor cells, infiltrative growth and the induction of DNA damage responses after tumor therapy. Hence, NFkB represents an excellent therapeutic target for neoplastic disease. However, previous attempts to tackle NFkB signalling in the clinic have produced inacceptable side effects. We have recently shown that the drug Cannabidiol (CBD; which is applied in pediatric neurology as Epidiolex) therapeutically modulates the NFkB pathway and thereby has efficient anti-tumor effects against a large range of GBM. Predictive biomarkers for CBD-sensitive GBM were obtained providing a basis for translational studies. In our current project we are now performing a prospective study with human GBM biopsies to rigorously test predictive biomarkers and genetic markers for CBD-sensitive tumor in pharmacological assays. Furthermore, we investigate in vitro and in vivo models for their transcriptomic, proteomic, genomic and epigenetic characteristics to identify pharmacological compounds that have synergistic therapeutic effects together with CBD and exert anti-neoplastic effects through modulation of NFkB signalling. This project will provide new therapeutic strategies to address the broad pathological roles of NFkB in neoplastic disease.