A new study from the University of Texas Southwestern Medical Center has large implications for the 0.03% of the population who lives with neurofibromatosis (NF1), one of the most common human genetic diseases. Dr. Lu Le and Dr. Zhiguo Chen, using a large multihead microscope at UT Southwestern, discovered the specific cell type responsible for large, disfiguring tumors called plexiform neurofibromas that occur in 30% of NF1 patients.
“This advance provides new insight into the steps that lead to tumor development and suggests ways to develop therapies to prevent neurofibroma formation where none exist today,” said Dr. Le in a news release from UT Southwestern. Along with Dr. Chen and collaborators, Dr. Le described their work in “Cells of Origin in the Embryonic Nerve Roots for NF1-Associated Plexiform Neurofibroma,” published in Cancer Cell.
Although the majority of plexiform neurofibromas are benign, there is a 10% risk of malignant transformation and subsequent fatality. To understand the mechanisms of tumor development and transformation, the research team traced a set of cells, known as GAP43+ PLP+ Schwann cell precursors, in embryonic nerve roots and discovered the origin of the tumors.
“If we can isolate and grow the cells of origin for neurofibromas, then we can reconstruct the biological steps that lead these original cells to tumor stage,” said Dr. Le, explaining the motivation of their work. “Once we know the critical steps in the process, then we can design inhibitors to block each step in an effort to prevent or slow tumor formation.”
In the study the team did not design an inhibitor for treatment, but they did use their findings to generate an animal model for preclinical drug screening. The team genetically engineered mice to hold the mutation responsible for NF1 and administered PD0325901, a highly selective pharmacological inhibitor of MEK, which is part of a pathway vital to tumor formation. Mice treated with PD0325901 experienced significantly slower tumor growth than non-treated mice, indicating the mouse model can be used to test therapies before they are used in clinical trials.
These results are vital to the health and longevity of afflicted patients, as there is no cure for this specific type of transformed tumors, known as malignant peripheral nerve sheath tumors (MPNSTs). The present results add to the momentum of research generated last year by Dr. Le’s research team that found MPNSTs could be reduced by administering BRD4 inhibitors. The team is currently working with a pharmaceutical company to bring the BRD4-inhibiting drug into clinical trials.
“This study addresses a fundamental question in the neurofibromatosis field,” concluded Dr. Le. “It points to the importance of stem cells and their immediate progenitors in the initiation of tumors, consistent with the notion that these neoplasms originate in a subset of primitive precursors and that most cells in an organ do not generate tumors.” By identifying these specific cells, scientists may be one step closer to better helping patients with MPNST.