The NF1 gene normally acts to prevent uncontrolled cell growth in nerves and to block tumor formation. When the NF1 gene mutates and loses function, “it’s like hitting the gas pedal on a car with no brakes,” according to Weiss. Cells in the nerves grow and accumulate abnormally.
Neurofibromas can grow to be quite large – unsightly and disfiguring as well as sometimes painful and dangerous. In some cases, large plexiform neurofibromas can turn into deadly malignant peripheral nerve sheath tumors (MPNSTs). Exactly what causes this malignant transformation remains unknown. Other than being able to perform the occasional surgery in certain cases, there still is no way to treat plexiforms or MPNSTs.
“Our goal is curative therapy. We want to prevent tumors from forming or completely ablate them.”
—Nancy Ratner, PhD
Although the recent MEK inhibitor study showed nominal ability to slow growth of MPNSTs in mice, the tumors refuse so far to yield to available treatments.
Still, many people with NF1 can live long lives. Weiss notes that NF1 tumors tend to grow slowly, so years can pass before they become problematic, if at all. Although an advantage for patients, slow tumor growth can be a challenge when trying to design a clinical trial.
Plexiform neurofibromas can remain stable for almost a year, making it difficult and time consuming to evaluate medicines that may only slow or prevent the growth of tumors rather than shrink them. NF1 patients would also need to be on medicines for longer periods of time compared to people with faster-growing tumors.
“It comes down to managing acceptable levels of risk for the patient,” Weiss says. “In cancer, where the result of not treating is death, you may be willing to take certain risks. In NF1, it can be a different set of considerations.”
CHALLENGES REMAIN IN SOLVING NF1 PUZZLE
Ratner has studied NF1 her entire career and produced milestone findings on how the disease process works. Although she is pleased to see clinical trials open for a drug that may be able to stop or shrink NF1 plexiform neurofibromas, it is only one part of the NF1 puzzle.
“Being able to manage the disease would be a huge step forward,” she says. “But our goal is curative therapy. We want to prevent tumors from forming or completely ablate them.”
Despite these remaining challenges, Ratner is hopeful about finding other pieces of the puzzle. She was there when good answers were far and few between, and when research more or less centered on dissecting patient tumor samples and analyzing them under a microscope. But technology such as bioinformatics and advanced MRI capabilities — along with talent and hard work — are producing new possibilities.
“The success we have seen gives me real hope that soon we will be able to identify drugs that really do melt these neurofibromas so they won’t come back,” Ratner says.
Her team also has a list of candidate molecular targets that might kill off MPNST cells. The results, however, are still early. “We need more verification before we can discuss it.”
—Story originally appeared in the Winter 2013 edition of Research Horizons.