Targeted Therapy for Neuroblastoma: ALK Inhibitors

Abstract

Treatment for neuroblastoma, the most common extracranial childhood tumor, spans a broad range of aggressiveness that mirrors the risk profiles of disease subtypes, with high-risk neuroblastoma still presenting a clinical challenge. Currently, most patients with relapsed neuro­blastoma die of disease and present a major challenge for treatment. New therapeutic options are urgently needed to improve patient survival. Activating mutations in the gene encoding the anaplastic lymphoma kinase (ALK) remain the most frequent druggable mutations identified in neuroblastomas to date. Preclinical data support an oncogene addiction of neuroblastoma cells to mutated ALK and demonstrate that ALK inhibitory therapy strongly combats tumor models. Most recently, pediatric phase I testing has been completed for the first approved ALK inhibitor, Crizotinib, showing very encouraging antitumoral results in neuroblastoma patients. Subsequently, an international phase I study with the second generation ALK inhibitor, LDK-378, will be launched that makes ALK inhibitory therapy also available to pediatric patients in Germany.

Zusammenfassung

Das Neuroblastom ist der häufigste extrakrani­elle Tumor des Kindesalters. Die Behandlung von Neuroblastomen der Hochrisikogruppe ist nach wie vor eine klinische Herausforderung, und die Prognose von Patienten mit einem Neuro­blastomrezidiv ist nahezu infaust. Aktivierende Mutationen im Gen der Anaplastischen Lymphomkinase sind die häufigsten Mutationen in Neuroblastomen, die einer zielgerichteten Therapie zugänglich sind. Präklinische Daten stützen die Hypothese einer Onkogenabhängigkeit der Neuroblastomzellen von mutierter Anaplastischer Lymphomkinase (ALK) und deuten auf eine hohe Effizienz einer Therapie hin, die auf die Inhibition von ALK abzielt. Kürzlich konnte bereits eine pädiatrische Phase-I-Studie mit dem ALK-Inhibitor Crizotinib mit guten Ergebnissen auch im Hinblick auf eine antitumorale Wirkung bei Neuroblastomen abgeschlossen werden. In den nächsten Wochen wird darüber hinaus eine internationale pädiatrische Phase-I-Studie mit einem ALK-Inhibitor der zweiten Generation, LDK-378, initiiert werden. Damit können erstmals auch in Deutschland pädiatrische Patienten in einer Studie mit einem ALK-Inhibitor behandelt werden.

Key words

pediatric cancer - crizotinib - LDK-378 - LDK378

Schlüsselwörter

pädiatrische Krebserkrankung - Crizotinib - LDK-378 - LDK378

• References

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