The researchers studied how mutations in the anaplastic lymphoma kinase (ALK) gene cause types of neuroblastoma. (Representational Image)
A powerful new drug with "unparalleled" strength against deadly forms of a childhood cancer that resist treatment has been identified by researchers.
Building on previous experiences in treating some refractory subtypes of neuroblastoma with the anticancer drug crizotinib, researchers from The Children's Hospital of Philadelphia (CHOP) have devised new treatments for stubbornly deadly forms of the childhood cancer neuroblastoma.
Usually appearing as a solid tumour in the chest or abdomen, neuroblastoma accounts for a disproportionate share of cancer deaths in children despite many recent improvements in therapy.
Neuroblastoma is particularly complex, with a bewildering variety of types and subtypes caused by separate and interacting gene mutations.
"Our preclinical results provide a strong rationale for fast-tracking this drug into clinical trials in children with neuroblastoma," said Yael P Mosse, an oncologist at CHOP.
The researchers studied how mutations in the anaplastic lymphoma kinase (ALK) gene cause types of neuroblastoma, stemming from their original 2008 discovery of the gene's role in most cases of rare, inherited neuroblastoma.
Subsequent research showed that abnormal ALK changes drive approximately 14 per cent of high-risk forms of neuroblastoma.
The researchers repurposed crizotinib, an ALK inhibitor, in clinical trials of children with neuroblastoma.
In children with neuroblastoma, different mutations within the ALK gene respond differently to crizotinib. One particular mutation, labelled F1174L, resisted crizotinib, so the researchers sought a new-generation, more effective ALK inhibitor.
They tested numerous next-generation ALK inhibitors, and their data allowed them to pursue for further investigation an agent called PF-06463922, currently being tested in a phase clinical trial of an ALK-driven subtype of lung cancer in adults.
That agent binds more tightly than crizotinib to the signalling kinases that drive cancer.
In the current study, PF-06463922 was more powerful than crizotinib in both neuroblastoma tumour cell cultures and in animal models - mice with implanted neuroblastoma tumours derived directly from human patients.
The researchers showed that PF-06463922 showed more profound inhibition of ALK than crizotinib, and at far lower concentrations.
The tumours 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 Mosse.
"The drug had very broad potency against a range of ALK mutations, so this could become the ALK inhibitor that is prioritised for frontline therapy in patients with ALK-driven neuroblastoma," she added.
The findings were published in the journal Cancer Discovery.