Neurofibromatosis Type 1 (NF1) is a genetic syndrome caused by an alteration in one copy of the NF1 gene. Patients with NF1 have increased activity of the Raf/MEK/ERK (MAPK) pathway, which activates cell growth and division, and therefore are more likely to develop tumors throughout the body. Up to 60% of patients will have a plexiform neurofibroma, a type of tumor that grows along peripheral nerves. In addition, patients with NF1 are oftentimes shorter and have lower weights and decreased bone density when compared to patients without NF1, especially when they have large plexiform neurofibromas. Previous studies using indirect calorimetry (IC) have shown that patients with NF1 are more likely to use lipids (fat) for energy, a finding that is commonly seen in patients who are underfed, even when they have adequate nutrition. These findings suggest that patients with NF1 and pNF have abnormal metabolism, although the underlying reason for this is not known. The results of this study will help provide this information.

MEK-inhibitors (MEKi) are being used to treat tumors that have increased activity in the MAPK pathway such as melanoma (a malignant skin cancer), lung cancer, and, more recently, pNFs in patients who have NF1. Our preliminary data show that patients with NF1 who are receiving treatment with MEKi are more likely to gain weight. In addition, our study of patient and mouse pNF plasma samples shows that there is a change in fat metabolism that favors fat storage over fat usage after MEKi treatment. Importantly, although most NF1 patients with pNFs will respond to treatment, the degree of response is different for each patient, with some patients having an excellent response and others having minimal to no response. Studies of melanoma have shown that patients with a high BMI, and patients who have a decrease in lipid and amino acid levels during MEKi treatment are more likely to respond. However, a biomarker that can identify NF1 patients with pNF who are most likely to respond to treatment is still needed. In this study, we plan to use a mouse model (Nf1flox/flox; Postn-cre) that develops pNF tumors and patient samples to learn more about baseline metabolism in NF1 and how metabolism changes both globally (liver and plasma) and within pNF tumors during treatment with MEKi. We plan to use this information to develop a metabolic biomarker that can ultimately be used to identify NF1 patients who are most likely to respond to MEKi treatment.

The results of this study have the potential to improve management of all patients with NF1. Right now, we know very little about why some patients with NF1 are more likely to burn fats for energy at baseline and have difficulty gaining weight. We also do not know what types of energy pNF tumors use to grow or what global and tumor-specific metabolic changes need to occur for patients to respond to MEKi treatment. Following this study, we will be able to answer these questions. In the short term (within 1-5 years of study completion), the information from this study could provide a metabolic biomarker that, once validated, can be used to help identify patients who are most likely to respond to MEKi treatment. This information will be very useful for treating physicians, who often have to make decisions about whether or not to continue MEKi treatment in patients who have not yet responded, but are experiencing side effects, with the hope that the patient will ultimately have a response. In the long term, information from this study can provide a baseline to help answer many other questions we have regarding metabolism in NF1, such as (1) the impact this has on life expectancy, (2) how metabolic (diet or supplement) treatments that be used to improve weight gain in patients with NF1 in general, or (3) whether adjuvant metabolic treatments, used along with MEKi, can improve toxicities and promote better treatment responses in patients with pNF. The results of this study have the potential to greatly improve the overall health and well-being of patients with NF1.