Researchers in pediatric oncology identified a powerful new drug with unparalleled strength against neuroblastomas that resist treatment with crizotinib. The study, based on work done in cultured cells and mouse models, appeared in Cancer Discovery (doi:10.1158/2159-8290.CD-15-1056).

“Our preclinical results provide a strong rationale for fast-tracking this drug into clinical trials in children with neuroblastoma,” said study leader Yael P. Mossé, MD, a pediatric oncologist at The Children’s Hospital of Philadelphia. “We expect to begin a clinical trial early this year.”

Mossé collaborated with Mark A. Lemmon, PhD, previously at the Perelman School of Medicine at the University of Pennsylvania, and currently at Yale University.

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Neuroblastoma usually appears as a solid tumor in the chest or abdomen; it accounts for a disproportionate share of cancer deaths in children, despite many recent improvements in therapy. Neuroblastoma is a particularly complex tumor, with a many types and subtypes caused by separate and interacting gene mutations.

Mossé and colleagues have completed extensive studies on how mutations in the anaplastic lymphoma kinase (ALK) gene cause types of neuroblastoma, building on their original 2008 discovery of the gene’s role in most cases of rare, inherited neuroblastoma. Subsequent research has shown that 14% of high-risk forms of neuroblastoma are driven by abnormal changes in the ALK gene.

Based on this knowledge, Mossé and other scientists with the Children’s Oncology Group were able to repurpose crizotinib, an ALK inhibitor, in clinical trials of children with neuroblastoma. Crizotinib is FDA approved to treat a subtype of lung cancer in adults caused by ALK gene abnormalities.

Different mutations within the ALK gene in pediatric neuroblastoma respond differently to crizotinib. For example, the mutation labelled F1174L resisted crizotinib, so Mossé’s team sought out a next-generation ALK inhibitor. After testing numerous next-generation ALK inhibitors, they had the data to pursue further investigation of an agent called PF-06463922. This agent is currently in a phase 1/2 clinical trial of an ALK-driven subtype of lung cancer in adults; it binds more tightly than crizotinib to the signaling kinases that drive cancer.

In this study, PF-06463922 was more effective than crizotinib in both neuroblastoma tumor cell cultures and in animal models (mice with implanted neuroblastoma tumors derived directly from human patients). Mossé, Lemmon, and colleagues showed that PF-06463922 demonstrated more profound inhibition of ALK than crizotinib, and at far lower concentrations. The tumors in the animals showed rapid, complete, and sustained regression.

“The responses we saw in animals were unprecedented in models of ALK-driven neuroblastoma, and bolsters the case for clinical development of this agent for treating children with this subtype of neuroblastoma,” said Mossé. “The drug had very broad potency against a range of ALK mutations, so this could become the ALK inhibitor that is prioritized for frontline therapy in patients with ALK-driven neuroblastoma.”