Experimental Local Therapy in High-Risk Neuroblastoma

尽管采用多模式治疗，但高风险神经母细胞瘤患者的预后仍然不利。通过全基因组测序分析未经治疗的高风险神经母细胞瘤显示出多样化的突变谱。它揭示了端粒酶逆转录酶基因（TERT）的新的复发性重排和众所周知的基因改变（如MYCN和ALK）。与没有突变的患者相比，TERT重排或MYCN扩增患者的临床病程都与较差的预后相关。如果TERT高表达（通过TERT重排或MYCN扩增）同时发生p53/RAS通路突变（例如ALK突变），则将患者定义为超高风险患者。这一组的预后甚至比高危组更差。端粒酶抑制剂伊美司他和6-硫代葡萄糖治疗显示肿瘤体积减少，TERT重排肿瘤动物存活率提高。在MYCN扩增的肿瘤中，这种效应在体内未见。因此，有必要阐明MYCN扩增的肿瘤（有或没有ALK突变）是否对端粒酶抑制剂的局部应用表现出更好的反应，通过丝豁免和三倍剂量。这将纳入原发性肾上腺肿瘤的切除手术。此外，我们还分析了端粒酶活性、增殖、凋亡潜能和DNA损伤。对潜在的新治疗药物进行实验将是开发高风险神经母细胞瘤个体化治疗策略的必要条件。

The prognosis of patients with high-risk-neuroblastoma still is unfavorable despite multimodal treatment. Untreated high-risk-neuroblastoma analyzed by whole-genome sequencing showed the diverse mutation spectrum. It revealed new recurrent rearrangements of the telomerase reverse transcriptase gene (TERT) and the well-known gene alterations (like MYCN and ALK). The clinical course of patients with TERT rearrangements or MYCN amplifications are both associated with a poorer outcome in contrast to patients without aberration. If a high TERT expression (by TERT rearrangements or by MYCN amplification) occurs in combination with a p53/RAS pathway mutation (for example ALK mutation), patients are defined as ultra-high-risk-patients. This group has an even worse prognosis than the high-risk-group.The treatment with telomerase inhibitors Imetelstat and 6-thio-dG showed a reduced tumor volume and a better survival of animals harboring tumors with a TERT rearrangement. In MYCN amplified tumors, this effect could not be seen in vivo. Thus, it is necessary to elucidate if tumors with MYCN amplification (with or without ALK mutation) show a better response to a local application of telomerase inhibitors by a silk waiver and a tripled dosage. This will be incorporated at the resective surgery of the primary adrenal tumor located. Furthermore, we analyze telomerase activity, proliferation, apoptotic potential and DNA damage of the treated tumors.Experiments with potential new therapeutic agents will be essential for the development of individualized treatment strategies in high-risk-neuroblastoma.