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Early trial results shrink pediatric neural tumors
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 rapidly prior to adolescence. Complete surgical removal of the tumors is rarely possible, and tumors not completely removed tend to grow back.
The primary aim of the clinical trial was to evaluate selumetinib toxicity and safety in patients with neurofibromatosis type 1, NF1, and other inoperable plexiform neurofibromas. Encouragingly, most of the selumetinib-related toxic effects were mild. At present, though, no therapies are considered effective for NF1 related large plexiform neurofibromas. However, the current trial showed a 20 percent reduction, some more, in tumor volume in over 70 percent of 24 child patients.
"Some may say that a 20 percent volume reduction is too small to be meaningful, but to me, just stopping the growth of these devastating tumors is an important achievement," said Dr. Widemann. "The difference we see in these patients is truly unprecedented."
The disease-causing gene for NF1 was first identified in 1990 by two independent teams, one of them led by NIH Director Francis S. Collins PhD MD, at that time Chief of Medical Genetics at the University of Michigan. The other team was led by Ray White PhD, Executive Director of the Huntsman Cancer Institute (HCI) at the University of Utah.
Trial enrollment began in September 2011 and 24 children (11 girls, 13 boys) participated. It was taken orally as a capsule twice daily continuously, over an average of 30 month cycles. The majority of patients are still continuing with therapy — some have for as long as five years — without observed adverse effect on their development or overall health.
Experiments in mice with similar neurofibromas confirmed inhibition of the MEK protein function in tumors. Inhibition of MEK protein dropped as quickly as two hours after taking the drug began. Additionally, animals receiving treatment with regular interruptions, still had tumor responses, indicating even limited MEK inhibition could iniate tumors to shrink.
In some patients, particularly after dose reduction, a loss of response to selumetinib and slow regrowth of tumors was observed. Researchers believe additional studies are warranted to characterize tumors that stop responding to selumetinib. An NCI selumetinib phase II trial for adults with NF1 is currently underway. Serial tissue samples are being taken which should provide information about possible mechanisms of resistance to selumetinib.
In this new trial, evaluations are being performed to assess the effect of selumetinib on plexiform neurofibroma related disfigurement, pain, quality of life, and function.
Experiments were conducted on mice which had developed neurofibromas as a result of genetic modifications performed at Cincinnati Children's Hospital in the laboratory of Nancy Ratner PhD. The National Cancer Institute (NCI) is part of the National Institutes of Health.
Reference: Widemann BC, et al. Activity of Selumetinib in Neurofibromatosis Type 1 Plexiform Neurofibromas. December 29, 2016. NEJM. DOI: 10.1056/NEJMoa1605943.
This research was supported by NCI's Center for Cancer Research and the Cancer Therapy Evaluation Program; by the Children's Tumor Foundation to Michael Fisher to support participating sites other than the NCI; and by AstraZeneca providing selumetinib and funding for the pharmacokinetic analysis.
About the National Cancer Institute (NCI): NCI leads the National Cancer Program and the NIH's efforts to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI website at cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER.
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Plexiform neurofibromas develop in up to 50 percent