Neurofibromatosis Type 1:
What is neurofibromatosis type 1 (NF1)?
Neurofibromatosis type 1 (NF1) is a rare genetic disorder caused by mutations in the NF1 gene, a gene responsible for the production of neurofibromin, a protein that acts as a brake in tumor development by keeping cells from growing too quickly. Absence or lack of neurofibromin results in a protein class called MEK1/MEK2 being overactive, causing rapid cell growth and increasing the risk of tumor development.
NF1 affects both children and adults and is often characterized by the presence of skin changes, such as café-au-lait (light brown) spots, tumor growth, bone abnormalities and neurological complications. NF1 symptoms and severity are different for each person.
What causes NF1?
In approximately 50% of cases, people inherit a mutated NF1 gene from a parent with NF1. In the other half of cases, people are born with a mutated NF1 gene even though neither of their parents has NF1. The mutated NF1 gene results in the absence or lack of neurofibromin.
What are plexiform neurofibromas (PN)?
Plexiform neurofibromas (PN) are a severe manifestation of NF1. They arise from peripheral nerves and can occur anywhere in the body, including the head and neck, extremities, areas around the spine, as well as deep in the body where they may affect organs. These tumors are characterized by aggressive growth, which is typically more rapid during childhood, and can cause severe pain, disfigurement, and debilitating loss of range of motion. PNs are non-malignant but in some patients (about 8-15%) they can evolve into a very severe and fatal malignant tumor called malignant peripheral nerve sheath tumors, or MPNST.
Who is at risk for NF1-associated plexiform neurofibromas (NF1-PN)?
It is estimated that NF1 affects 1 in 3,000 individuals worldwide and that there are approximately 100,000 people in the United States living with the disease. About 30-50% of people living with NF1 progress to develop NF1-PN. NF1-PN are most often diagnosed in the first two decades of life.
Clinical Representation of Neurofibromas
Cutaneous neurofibromas are characterized by flat, light brown spots, also called ‘café-au-lait spots,’ and are often seen in earlier stages of NF1.
Plexiform neurofibromas are peripheral nerve sheath tumors that can grow in an infiltrative pattern, making them challenging to surgically remove.
How is NF1-PN treated?
Historically many people with NF1-PN were treated by having their tumors surgically removed; however, due to how these tumors grow on nerve cells it is challenging to successfully remove these tumors without serious complications, such as permanent nerve damage and further disfigurement.
SpringWorks is testing an investigational MEK inhibitor, mirdametinib, in a Phase 2b clinical trial, known as the ReNeu trial. Mirdametinib is under development as an oral, small molecule, selective inhibitor of MEK1 and MEK2, which play key roles in the MAPK signaling pathway—in other words, mirdametinib is designed to target a key pathway in the body that is known to play a role in many types of cancers and rare diseases.