Puberty and plexiform neurofibroma tumor growth in patients with neurofibromatosis type I.

OBJECTIVE: To assess the relationship between pubertal progression and change in plexiform neurofibroma (PN) burden over time in pediatric and young adult patients with neurofibromatosis type 1 and PNs. STUDY DESIGN: Analyses accounted for sex, age, race, and chemotherapy. Forty-one patients with neurofibromatosis type 1 (15 female and 26 male patients) were studied at the National Institutes of Health. Tanner stage, testosterone, progesterone, estradiol, insulin-like growth factor -1, luteinizing hormone, and follicle-stimulating hormone were assessed. Tumor volume was measured using magnetic resonance imaging and lesion detection software developed locally. Patients were divided into 2 groups based on whether they were actively progressing through puberty (n = 16) or were peripubertal (n = 25) and were followed for an average of 20 months. Tumor growth rates in the puberty and peripubertal group were analyzed for a subset of patients. RESULTS: There was no statistically significant difference in tumor burden change over time (cm(2)/kg per month) between the pubertal and peripubertal groups (-0.16 ± 0.34 vs 0.03 ± 1.8, P = .31) and in the PN growth rates before and during puberty (P = .90). Change in tumor volume/patient weight/time did not correlate with testosterone change/time in males or estradiol change/time in females. CONCLUSION: These findings support that hormonal changes of puberty do not accelerate PN growth. Additional long-term follow-up of patients is necessary to further characterize the interaction between puberty and tumor growth.

MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors.

Neurofibromatosis type 1 (NF1) patients develop benign neurofibromas and malignant peripheral nerve sheath tumors (MPNST). These incurable peripheral nerve tumors result from loss of NF1 tumor suppressor gene function, causing hyperactive Ras signaling. Activated Ras controls numerous downstream effectors, but specific pathways mediating the effects of hyperactive Ras in NF1 tumors are unknown. We performed cross-species transcriptome analyses of mouse and human neurofibromas and MPNSTs and identified global negative feedback of genes that regulate Ras/Raf/MEK/ERK signaling in both species. Nonetheless, ERK activation was sustained in mouse and human neurofibromas and MPNST. We used a highly selective pharmacological inhibitor of MEK, PD0325901, to test whether sustained Ras/Raf/MEK/ERK signaling contributes to neurofibroma growth in a neurofibromatosis mouse model (Nf1(fl/fl);Dhh-Cre) or in NF1 patient MPNST cell xenografts. PD0325901 treatment reduced aberrantly proliferating cells in neurofibroma and MPNST, prolonged survival of mice implanted with human MPNST cells, and shrank neurofibromas in more than 80% of mice tested. Our data demonstrate that deregulated Ras/ERK signaling is critical for the growth of NF1 peripheral nerve tumors and provide a strong rationale for testing MEK inhibitors in NF1 clinical trials.