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Feb 02 2016

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Scientists Discover a Better ALK Inhibitor to Treat Neuroblastoma

neuroblastomaPediatric cancer researchers at The Children’s Hospital of Philadelphia believe they have succeeded in their search for a powerful next-generation drug for neuroblastoma tumors with mutations in the anaplastic lymphoma kinase (ALK) gene associated with the cancer. Based on their preclinical findings, they are fast-tracking the launch of a clinical trial this year.

Usually appearing as a solid tumor in the chest or abdomen, neuroblastoma accounts for a disproportionate share of cancer deaths in children, despite many recent improvements in therapy.

The search for better ALK inhibitors originated when, in 2008, CHOP pediatric oncologist Yael Mossé, MD, and colleagues identified ALK mutations as a driver of most cases of rare, inherited neuroblastoma. Subsequent research showed that abnormal ALK changes drive approximately 14 percent of high-risk forms of neuroblastoma.

Based on this knowledge, scientists including Dr. Mossé in the multicenter Children’s Oncology Group were able to repurpose crizotinib, an ALK inhibitor already approved to treat adults with lung cancer, in clinical trials of children with neuroblastoma. But they found that different mutations within the ALK gene in neuroblastoma responded differently to crizotinib, and a mutation labelled F1174L was resistant to the drug.

Dr. Mossé’s team reported in January in the journal Cancer Discovery that they found a highly promising next-generation ALK inhibitor that outperformed crizotinib in preclinical models. In this study, Dr. Mossé collaborated with Mark A. Lemmon, PhD, previously at the Perelman School of Medicine at the University of Pennsylvania (where Dr. Mossé is also an assistant professor), and currently at Yale University.

They tested numerous next-generation ALK inhibitors, and their data allowed them to pursue for further investigation an agent called PF-06463922. This compound was more powerful than crizotinib in both neuroblastoma tumor cell cultures and in animal models — mice with implanted neuroblastoma tumors derived directly from human patients. Dr. Mossé, Dr. Lemmon, and colleagues showed that PF-06463922 showed 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 bolster the case for clinical development of this agent for treating children with this subtype of neuroblastoma,” Dr. Mossé said. “The drug had very broad potency against a range of ALK mutations, so this could become the ALK inhibitor that is prioritized for integration into frontline therapy in patients with ALK-driven neuroblastoma.”

For more information, see the CHOP press release about the next-generation ALK inhibitor.

Dr. Mossé is also principal investigator of the NEPENTHE trial, a precision medicine clinical trial recently announced for relapsed/refractory neuroblastoma that uses a novel dynamic design, which allows researchers to quickly translate findings from the lab based on the evolving individual characteristics of each patient’s tumor to test combination therapies that may speed up discovery. For more information, see CHOP Research’s Bench to Bedside publication and the CHOP press release about the NEPENTHE trial.

 

Permanent link to this article: http://blog.research.chop.edu/scientists-discover-a-better-alk-inhibitor-to-treat-neuroblastoma/