Experimental therapy for neurofibromatosis I shows promise

Cancer drug shrinks some plexiform neuromas

A drug used to treat chronic myeloid leukemia (CML) and certain gastrointestinal tumors can shrink some difficult-to-treat and potentially life-threatening tumors associated with neurofibromatosis type 1 (NF1), one of the most common neurological disorders caused by mutations in a single gene.

In a small phase 2 study published online in The Lancet Oncology, researchers from Indiana University in Indianapolis, and other institutions, say the oral drug imatinib mesylate, marketed as Gleevec, provided relief to a significant proportion of participating NF1 patients with plexiform neurofibromas (Robertson et al., 2012).

Plexiform neurofibromas are noncancerous tumors that develop in the peripheral nervous system. Neurofibromas become dangerous when they grow too large and too close to vital organs or the windpipe. These tumors have been nearly impossible to treat effectively because as benign tumors, they do not respond to chemotherapy. Neurofibromas are often challenging to remove surgically because of their location, while high-dose radiation can induce sarcoma in the tumor bed.

“The findings of this study provide the first evidence of an effective therapy for a subgroup of NF1-related plexiform neurofibromas,” the authors say. This study and others that preceded it demonstrate the value of translational medicine and present a model for testing other drugs in mouse models before moving into clinical trials, they write.

The Road to Discovery

Research on the use of imatinib for NF1 human patients with plexiform neurofibromas gathered steam when a team led by Luis Parada, PhD, at the University of Texas Southwestern Medical Center in Dallas, found that disrupting the Nf1 gene in mouse peripheral nervous system Schwann cells—which protect against disease and trauma—was not enough to generate tumors. Tumor formation also requires reduced Nf1 gene expression in non-tumor cells, the team concluded (Zhu et al., 2002).

In 2008, other researchers found that mast cells of the inflammatory system must infiltrate neurofibroma to help propagate tumor growth. Researchers also established that plexiform neurofibroma formation requires mutations in both copies of the Nf1 gene in Schwann cells, but in just one copy of the gene in mast cells. A key finding was that Schwann cells use a signaling system protein called c-kit to recruit the mast cells as part of tumor development.

The researchers, led by D. Wade Clapp, MD, at Indiana University, concluded imatinib might be useful in treating plexiform neurofibromas because the drug acts on the c-kit receptor (Yang et al., 2008). Dr. Clapp and his team used imatinib to reduce by 80% a three-year-old child's plexiform neurofibroma that was compressing her airway.

The Current Study

That success gave rise to the current study. Dr. Clapp and his team administered imatinib to 3 6 NF1 patients with significant neurofibromas. For six months, children received 220 mg/m2 of imatinib twice a day, and adults received 400 mg twice a day. Six patients, or 17%, had a decrease in tumor volume of at least 20% after at least six months.

Researchers monitored 69 tumors. The most common side effects were rash, swelling, and weight gain, while serious side effects included reversible drops in white blood cell count, high blood sugar, and, in one patient, increases in aminotransferase concentrations.

Nine of the 13 patients who dropped out of the study did so because of side effects. According to the study's first author, Kent A. Robertson, MD, PhD, Associate Professor of Pediatrics at the Indiana University School of Medicine in Indianapolis, patients with plexiform neurofibromas have a lower tolerance for side effects than do malignant tumor patients because plexiform neurofibromas grow very slowly, so patients can live with them for years.

More Research

To learn how to best modify imatinib dosage so it is both effective and tolerable, Dr. Robertson and his team are studying imatinib dosing regimens that incrementally increase the dose over a six-month, or 24-month, period to determine the clinical benefit. While the researchers won't report results until next year, Dr. Robertson says patients tolerate imatinib better under the dose acceleration scenario, and that toleration rates vary.

This dosing study addresses questions about heterogeneity in patients with these tumors, says David H. Gutmann, MD, PhD, the Donald O. Schnuck Family Professor of Neurology, and Director of the Washington University Neurofibromatosis Center in Saint Louis, Missouri, who adds, “patients with plexiform neurofibromas aren't all the same.”

Human studies of imatinib raise good questions for future research on plexiform neurofibromas, says David Viskochil, MD, PhD, Professor of Pediatrics at the University of Utah in Salt Lake City, including how long and at what intervals patients should take imatinib. Answering this, and identifying which patients will respond to the drug, would be helpful.

Determining which patient will respond to a drug to treat plexiform neurofibromas is tricky, says Dr. Robertson. That's because each plexiform is an independent tumor, as opposed to metastasized tumors that are genetically the same as the original tumor. “So each plexiform neurofibroma, even within the same patient, will behave differently according to its own genetic and growth characteristics,” he says.

Other Drugs

Dr. Robertson and his group are also studying nilotinib and sunitinib—both kinase inhibitors—for the treatment of plexiform neurofibromas. Other research groups, including The Neurofibromatosis Clinical Trials Consortium, funded by the U.S. Department of Defense, are studying a rapamycin derivative, sirolimus, that inactivates the mTOR complex. Other groups are looking at MEK inhibitors.

All of this research requires understanding not only the RAS pathway, which involves proteins that control an intracellular signaling network, but also the microenvironment that surrounds it, Dr. Robertson notes.

Research on these drugs, as well as imatinib, could eventually allow geneticists and other specialists to better tailor care for individual patients. “If we perform these studies correctly, we may be able to deliver personalized medicine for children and adults with NF1,” Dr. Gutmann says.