Researchers identify oncogenic pathway that leads to high-risk neuroblastoma

Researchers have identified an abnormal molecular signaling network that generates a high-risk form of neuroblastoma. These findings could be used to develop effective targeted treatments, researchers predict. Their study was published online October 15, 2015 in Cancer Cell.

Patients with high-risk neuroblastoma undergo intense multimodal treatment; however, cure rates remain below 50%, and survivors are burdened with significant long-term morbidities. So, researchers are focused on finding more effective therapies.

“As we improve our knowledge of different biological pathways followed by genes and proteins in this complex disease, we will be better equipped to develop appropriate drug combinations to treat neuroblastoma,” said co-senior author Sharon J. Diskin, PhD, a pediatric cancer researcher at The Children’s Hospital of Philadelphia (CHOP), in Philadelphia, PA.

This current study builds on the research team’s 2012 discovery, in which they identified the LIN28B gene as an oncogenic driver in high-risk neuroblastoma. The gene was already known to play roles in different cancers, but their study was the first to link it to neuroblastoma.

In this investigation, the researchers explored specific mechanisms by which LIN28B drives neuroblastoma. The researchers performed cell analyses of 250 tumor samples from neuroblastoma patients, as well as studies in animal models.

They showed that variants in the LIN28B gene generate abnormal signals that regulate the RAN gene. Consequently, the RAN gene becomes overactive and produces higher levels of RAN protein, causing cells to grow out of control in tumors. In addition, LIN28B and RAN signaling directly and indirectly promote expression of the AURKA gene, which is known to play key roles in neuroblastoma and other cancers.

Collectively, LIN28B-RAN-AURKA signaling drives neuroblastoma oncogenesis, the researchers concluded.

This finding raises the possibility that combined targeting of these pathways represents therapeutic opportunities in neuroblastoma, the authors noted.

“In preclinical and clinical studies, some existing anticancer drugs show desired effects against components of these pathways,” said first author Robert Schnepp, MD, PhD, an instructor and attending physician in the Division of Oncology at CHOP. “Our research offers opportunities to develop possible drug combinations to be tested in future clinical trials.”