Targeting ALK in neuroblastoma--preclinical and clinical advancements

Abstract

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.

Figure 1

Schematic representation of ALK protein structure and mutations found in neuroblastoma. The low-density lipoprotein domain, two MAM domains, and the transmembrane and kinase domains of ALK are shown. R1275, F1174 and F1245 are three most common ALK mutations in neuroblastoma; the frequency of these mutations are provided in parenthesis. Other low frequency mutations (>20) are denoted with an asterisk. The tyrosine kinase inhibitor crizotinib is in clinical trials and other second-generation ALK inhibitors are in clinical development. ALK-targeting antibodies are also being developed.

Figure 2

Timeline depicting the milestones leading to the clinical testing of the ALK inhibitor crizotinib targeting the full-length ALK in neuroblastoma (above) and translocated ALK in non-small-cell lung cancer (below).