Targeting ALK in neuroblastoma—preclinical and clinical advancements

Abstract

Neuroblastoma is a debilitating disease and a leading cause of childhood cancer deaths. The discovery of ALK as a mutated oncogenic receptor in neuroblastoma has provided an attractive target for innovative therapies. In this article, Mosse and Carpenter review the preclinical and clinical advances in ALK-targeted therapies for neuroblastoma and discuss the emerging challenges. Despite improvements in cancer therapies in the past 50 years, neuroblastoma remains a devastating clinical problem and a leading cause of childhood cancer deaths. Advances in treatments for children with high-risk neuroblastoma have, until recently, involved addition of cytotoxic therapy to dose-intensive regimens. In this era of targeted therapies, substantial efforts have been made to identify optimal targets for different types of cancer. The discovery of hereditary and somatic activating mutations in the oncogene ALK has now placed neuroblastoma among other cancers, such as melanoma and non-small-cell lung cancer (NSCLC), which benefit from therapies with oncogene-specific small-molecule tyrosine kinase inhibitors. Crizotinib, a small-molecule inhibitor of ALK, has transformed the landscape for the treatment of NSCLC harbouring ALK translocations and has demonstrated activity in preclinical models of ALK-driven neuroblastomas. However, inhibition of mutated ALK is complex when compared with translocated ALK and remains a therapeutic challenge. This Review discusses the biology of ALK in the development of neuroblastoma, preclinical and clinical progress with the use of ALK inhibitors and immunotherapy, challenges associated with resistance to such therapies and the steps being taken to overcome some of these hurdles.