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ALK inhibitor may overcome treatment resistance in pediatric neuroblastoma

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Pediatric oncologists at The Children’s Hospital of Philadelphia (PA, USA) have identified a powerful new drug that could combat crizotinib resistance in ALK-driven pediatric neuroblastoma.

The success of the preclinical results, which were published recently in Cancer Discovery, may result in a fast-tracking of the drug into clinical trials.

Despite recent therapeutic advances, neuroblastoma – a complex cancer, with various types and subtypes – still accounts for a large number of pediatric cancer deaths.

In 2008, lead investigator Yael P Mossé, a pediatric oncologist at The Children’s Hospital of Philadelphia, and her colleagues discovered the role of the ALK gene in most cases of rare inherited neuroblastoma. Since this time, they have spent many years studying the mutations that arise in the gene, which are known to drive approximately 14% of high-risk forms of neuroblastoma.

Following this research, Mossé and other scientists within the Children’s Oncology Group repurposed crizotinib, an FDA-approved ALK inhibitor, and tested the drug in clinical trials of children with neuroblastoma. Crizotinib has been previously approved to treat adults diagnosed with a subtype of lung cancer that arises from abnormalities in ALK gene.

Children carrying a particular mutation, labelled F1174L, demonstrated resistance to crizotinib. To attempt to overcome this crizotinib resistance, the team tested next-generation ALK inhibitors, and finally pursued the agent PF-06463922.

PF-06463922 binds to the cancer-driving signaling kinases with more strength than crizotinib, and is currently being investigated in Phase I/II clinical trials for an ALK-driven subtype of lung cancer.

In the present study, PF-06463922 was tested in both neuroblastoma tumor cell cultures and in animal models implanted with human tissue. It reported to be more effective at inhibiting ALK than crizotinib, and at lower concentrations. The tumors in the animal model demonstrated a rapid and complete response, and this regression was sustained.

Mossé commented: “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.

“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,” she continued.

Sources: Infarinato NR, Park JH, Krytska K et al. The ALK/ROS1 inhibitor PF-06463922 overcomes primary resistance to crizotinib in ALK-driven neuroblastoma. Cancer Discovery. DOI: 10.1158/2159-8290.CD-15-1056; Children’s Hospital of Philadelphia press release

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