Neuroblastoma, ALK, PI3-Kinase and mTOR pathways: Tumor's embryonic mimicry and new hopes for the management of neuroblastoma with tyrosine kinase inhibitor - immunestimulant cocktails

Neuroblastoma, the most common extracranial solid cancer in childhood and the most common cancer in infancy can exert a grave course. CD246/ALK (Anaplastic Lymphoma Kinase) is an important protein in neurodevelopment and one of the most important therapeutic targets in neuroblastoma biogenesis. Since the discovery of the oncofetal antigens in 1970's, it is well established that tumors reactivate embryonic genes for growth, invasion, angiogenesis and escape from immuno-surveillance. Crizotinib (Xalkori(R), Pfizer) the aminopyrimine type inhibitor of ALK could provide significant clinical benefits in malignancies with upregulated ALK activity. 

It is recently established that the combined inhibition of PI3-Kinase and mTOR pathways significantly augments crizotinib efficacy to prolong survival in animal models of neuroblastoma. Drugs such as NVP-BEZ235 (Novartis) and LY3023414 (Lilly) are promising drugs under development to block both mTOR and PI3K pathways. Since some forms of neuroblastomas could also exert simultaneous regression, it is also plausible to assume that some pathways involving in dedifferentiation of neural progenitors to neuroblastoma cancer stem cells may trigger expression of antigens, which would cause enhanced recognition by immune cells rather than immunosuppression. Thus, I here propose that combining ALK inhibitors, dual inhibitors of mTOR and PI3K pathways and immunestimulating drugs may provide a powerful synergistic approach in management of neuroblastomas with high risk profile.