Years of laboratory research by the team of Cincinnati Children’s cancer biologist Nancy Ratner, PhD, has led to a new study in the New England Journal of Medicine showing targeted molecular therapy for NF1 plexiform neurofibromas helps children with the genetic disorder.
In a multicenter phase I clinical trial of a new oral drug, selumetinib, children with the common genetic disorder neurofibromatosis type 1 (NF1) and plexiform neurofibromas (tumors of the peripheral nerves) tolerated the drug and in most cases responded to it with tumor shrinkage. The trial, which included 24 patients, was led by Brigitte C. Widemann, MD, acting chief of the National Cancer Institute’s (NCI) Pediatric Oncology Branch, and was sponsored by NCI’s Cancer Therapy Evaluation Program. NCI is part of the National Institutes of Health.
Ratner is a co-investigator on the NEJM study (published online Dec. 29). Ratner and her team in the Cancer and Blood Diseases Institute have been trying for decades to unlock the secrets of NF1 – long considered a genetic disorder without effective treatment options.
NF1 affects 1 in 3,000 people. Plexiform neurofibromas develop in up to 50 percent of people with NF1. The majority of these tumors, which can cause significant pain, disability, and disfigurement, are diagnosed in early childhood and grow most rapidly prior to adolescence. In some cases they turn into deadly malignant peripheral nerve sheath tumors.
Ratner’s team first reported in a 2013 study in the Journal of Clinical Investigation that blocking a single, critical protein in the NF1 molecular process (MEK) is effective at shrinking plexiform neurofibromas in mouse models of the disorder. The AstraZeneca drug tested in the new NCI-led clinical trial, selumetinib, inhibits the MEK protein.
“The clinical trial shows that a single agent given at low dose inhibits MEK and significantly shrinks even very large plexiform neurofibromas,” Ratner said. “Also, a genetically engineered mouse model of neurofibromas developed at Cincinnati Children’s predicted the efficacy of MEK inhibition in the human tumors. Having a mouse model that is predictive for treatment response in humans is rare, and may identify even more effective therapies.”
The NEJM study included experiments in mice with similar neurofibromas and confirmed the inhibition of the MEK protein function in the tumors. Inhibition of the MEK protein was found as early as two hours after drug administration. In addition, the animals received treatment with regular interruptions and still showed tumor shrinkages. This indicates that even limited MEK inhibition could cause tumor shrinkage in this disease.
“In the future, we may wish to look at intermittent dosing in patients to minimize toxicity and retain maximal outcomes,” said Widemann.
The genetically engineered mouse model that was key to recent research breakthroughs was developed with funding from the National Institute of Neurological Disorders and Stroke. Much of Ratner’s research using the mouse model was funded by the Children’s Tumor Foundation and the Neurofibromatosis Therapeutic Acceleration Program.
Other Cincinnati Children’s co-investigators on the NEJM study are oncologist Brian Weiss, MD, who led the Cincinnati Children’s arm of the clinical trial, Elizabeth Schorry, MD, who heads the medical center’s NF1 patient clinic, and Lindsey Aschbacher-Smith, MS, Tilat Rizvi, PhD, and Jianqiang Wu, MD, who evaluated mouse tumors.