Therapeutically Actionable Genetic Aberrations

The heterogeneous clinical behavior and biology of neuroblastoma as well as the relative paucity of somatic mutations render the development of effective therapies a challenge. As the genetic landscape of neuroblastoma is unraveled, certain aberrations have emerged as potent targets in the clinic. However, the challenge lies in the ability to determine the functional relevance of such mutations and to determine which ones to target and with what agents. The identification of treatment-sensitive mutations in the ALK tyrosine kinase receptor that opened neuroblastoma to targeted therapy offers a hallmark example of a therapeutically actionable genetic aberration. Attempts at targeting the effects of the oncogenic driver, MYCN, are also emerging—in terms of strategies to block its transcriptional program and its protein stabilization. However, the advent of targeted therapy has also ushered in the concept of resistance that needs to be addressed preemptively. This chapter summarizes the current status of therapies under investigation and in clinical use to target genetic aberrations in neuroblastoma.