As a new year begins, plans are underway for the 8^th Annual Rare Disease Genomics Symposium to be held on February 26^th and 27^th.  The two-day event will be virtual this year to limit the spread of COVID-19, and that, in turn, will make it more accessible to participants, even those who reside far from Birmingham. As in previous years, the Symposium is designed to share information about the role of genomics in the diagnosis and treatment of rare disease with members of the community and healthcare practitioners who are non-genetic specialists. While the event is not specific to neurofibromatosis, NF1 is a rare disorder that benefits from diagnostic and therapeutic approaches used in the management of other rare disorders. To view the full Symposium agenda or to register, please visit: 8th Annual Rare Disease Genomics Symposium - School of Medicine - Genetics | UAB

The focus of this month’s blog post is to discuss the difference in treatment options for plexiform neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). While medications called MEK inhibitors can help treat plexiform neurofibromas in approximately 2/3 of individuals with NF1, treatment options for MPNSTs are more limited. Many patients understandably want to know whether MEK inhibitor drugs will successfully treat MPNSTs. These tumors occur in about 10% of people with NF1 and represent one of the few potentially life-threatening complications of the condition. The tumors occur mostly in teens and young adults with NF1 and usually arise from pre-existing plexiform or nodular neurofibromas. Atypical neurofibromas, which have distinct clinical and pathological features, may be a precursor to the development of an MPNST. These atypical tumors appear as homogenous nodules that, if superficial, have a firm consistency when palpated. MEK inhibitor drugs are not currently part of the standard treatments for MPNSTs, although clinical trials are underway to investigate the effectiveness of using MEK inhibitor drugs in combination with other medications to treat these tumors. The approach of using several biological compounds together as part of a treatment regimen is common in cancer treatment.

The difference in treatment options for plexiform neurofibromas and MPNSTs is based on fundamental differences in the genetic drivers of these tumors. Plexiform neurofibromas have the NF1 germline mutation, which is a genetic change that occurs in the egg or sperm cell that is passed directly from a parent to a child or arises due to a new mutation. This NF1 mutation is present in every cell of the body. For a neurofibroma to develop, a random genetic mutation must occur to the second copy of the NF1 gene in the tissue that will become the neurofibroma. (Remember that everyone has two copies of every gene, other than those on the X or Y chromosome.) This is referred to as the “second hit” mutation.  Except for these genetic changes to the NF1 gene, plexiform neurofibromas are usually genetically normal. MEK inhibitors block a component of the Ras/MAPK signaling pathway, called MEK, that is hyperactive in cells in which both copies of the NF1 gene have been impaired. Selumetinib is a MEK inhibitor drug recently approved by the FDA for treatment of plexiform neurofibromas in children and is the first medication specifically approved for use with NF1.

In contrast to plexiform neurofibromas, MPNSTs have numerous genetic changes, or mutations, that are characteristic of cancer. Cancer cells are fueled by an accumulation of genetic changes that drive altered cells to divide rapidly and spread throughout the body. The genetic changes in MPNSTs make these tumors difficult to control. While chemotherapy is still useful in treatment, these tumors continue to acquire rapid genetic changes that often cause them to develop resistance to chemotherapy and other traditional cancer treatments after a period of time.

Due to the features of MPNSTs that present challenges for treatment, the question is: What are the treatment options for MPNSTs?  Current treatments usually include surgery and may also include radiation or chemotherapy.  Looking to the future, there are at least three possible areas for treatment for future development.

• Genome sequencing provides information about the genetic landscape of malignant tumors, helping to identify genes that are drivers of these tumors. Using this information, therapies may be developed that effectively target these genes.
• Immunotherapy, which trains the individual’s immune system to attack tumors, is an important new area of potential treatment, though not yet tested extensively on MPNSTs.
• Because MPNSTs are difficult to treat, early detection may be the best way to treat these tumors. It is important to report instances of chronic pain or rapidly growing tumors. Studies are underway to find better indicators of tumors that have a potential to become malignant to facilitate early detection and treatment.