A research team from the Medical University of Vienna has discovered, through genome sequencing, that the protein ALK and the cancer gene PIM1 are involved in the development of neuroblastoma, a rare form of malignant tumor, primarily affecting children.1 Their study also found that targeted cancer treatment using an ALK inhibitor in combination with a PIM1 inhibitor can increase the chances of survival of children with an unfavorable prognosis.
Neuroblastoma, one of the most common and lethal types of solid childhood cancer, is a tumor of the peripheral nervous system. It occurs in approximately 10% of childhood cancer cases, with 90% of the sick children being under the age of 6. The course of the disease can differ greatly, depending upon the clinical picture and genetic mutation of the cancer cells. For example, the tumor can spontaneously regress, but equally there can be metastasis and recurrences with an unfavorable prognosis.
Standard treatments include surgery, high-dose chemotherapy, or radiotherapy but, in the event of recurrence, the chances of 5-year survival are not high. For a long time, the Medical University of Vienna’s research team, led by molecular pathologist Lukas Kenner, MD, has been studying a specific protein, anaplastic lymphokinase, ALK, in relation to the development of neuroblastoma in children. This protein is found to have mutated in approximately 14% of young patients. Small molecular ALK inhibitors, which are already approved for the treatment of ALK-positive lung cancer, are currently undergoing clinical trials for neuroblastoma patients with the mutated ALK gene. Preclinical studies confirm therapeutic efficacy, but some tumors develop resistance to ALK inhibitors.
The team’s research is now focusing on developing new treatment options on a molecular biological basis. The goal is to exploit molecular structures that are essential for tumor development. Working with Suzanne Turner, PhD, of Addenbrooke’s Hospital at the University of Cambridge, Kenner’s team tested the therapeutic effect of inhibitors for ALK mutations in children with recurrent neuroblastoma.
Genome sequencing of the tested patients revealed that the cancer gene PIM1 is also activated in neuroblastoma. The team is now investigating a therapeutic approach that involves deactivating this protein, which can be done using a targeted cancer therapy in the form of combined administration of ALK and PIM1 inhibitors. Currently, no drugs are licensed specifically for targeting PIM1, but preclinical studies are being conducted to investigate PIM1 and ALK inhibitors.
- Trigg RM, Lee LC, Prokoph N, et al. The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status. Nat Commun. 2019;10(1):5428; doi: 10.1038/s41467-019-13315-x.
Human neuroblastoma cells: nuclei are stained in red, microfilaments are in green. Photo © Volha Vshyukova, courtesy Dreamstime (ID 75388631).