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Neurofibromatosis involves activation of the RAS pathway. Inhibition of MEK, a component of the pathway, with selumetinib was performed in 50 children with inoperable disease. A total of 70% had a response, which was maintained in the majority for more than a year. Pain relief, improved function, and higher quality of life were also observed.

Plexiform neurofibroma is a complication of the NF1 mutation in neurofibromatosis that results in overactivity of the RAS pathway. Selumetinib, a mitogen-activated protein kinase (MAPK) kinase inhibitor, induced tumor regressions in a majority of patients. Neurofibromatosis type 1 is a common genetic disorder that is characterized by multiple manifestations including tumors of the nervous system. 1 , 2 Plexiform neurofibromas develop in 20 to 50% of persons with neurofibromatosis type 1 and can cause substantial complications including pain, functional impairment, disfigurement, and malignant transformation. 3 – 7 Most plexiform neurofibromas are diagnosed in early childhood and grow most rapidly during this period. 8 , 9 Complete surgical resection of these tumors is often not feasible, and regrowth of the tumor after incomplete surgical resection has been observed. 10 , 11 The NF1 product neurofibromin functions as a negative regulator of RAS activity. Lack . . .

Neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNs) are progressive, multicellular neoplasms that cause morbidity and may transform to sarcoma. Treatment of Nf1 fl/fl ; Postn -Cre mice with cabozantinib, an inhibitor of multiple tyrosine kinases, caused a reduction in PN size and number and differential modulation of kinases in cell lineages that drive PN growth. Based on these findings, the Neurofibromatosis Clinical Trials Consortium conducted a phase II, open-label, nonrandomized Simon two-stage study to assess the safety, efficacy and biologic activity of cabozantinib in patients ≥16 years of age with NF1 and progressive or symptomatic, inoperable PN ( NCT02101736 ). The trial met its primary outcome, defined as ≥25% of patients achieving a partial response (PR, defined as ≥20% reduction in target lesion volume as assessed by magnetic resonance imaging (MRI)) after 12 cycles of therapy. Secondary outcomes included adverse events (AEs), patient-reported outcomes (PROs) assessing pain and quality of life (QOL), pharmacokinetics (PK) and the levels of circulating endothelial cells and cytokines. Eight of 19 evaluable (42%) trial participants achieved a PR. The median change in tumor volume was 15.2% (range, +2.2% to −36.9%), and no patients had disease progression while on treatment. Nine patients required dose reduction or discontinuation of therapy due to AEs; common AEs included gastrointestinal toxicity, hypothyroidism, fatigue and palmar plantar erythrodysesthesia. A total of 11 grade 3 AEs occurred in eight patients. Patients with PR had a significant reduction in tumor pain intensity and pain interference in daily life but no change in global QOL scores. These data indicate that cabozantinib is active in NF1-associated PN, resulting in tumor volume reduction and pain improvement. Cabozantinib, an inhibitor of multiple receptor tyrosine kinases, has efficacy in a mouse model of neurofibromatosis type I and has clinical activity in reducing plexiform neurofibroma volume in a phase II trial of patients with NF1.

Background Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. Up to 50% will be refractory to conventional chemotherapy. It is now known that the majority of PLGG have activation of the MAPK/ERK pathway. The same pathway is also activated in plexiform neurofibromas (PNs) which are low-grade tumors involving peripheral nerves in patients with neurofibromatosis type 1 (NF1). These lesions are known to be refractory to chemotherapy. Specific MEK inhibitors such as trametinib are now available and have been approved for other cancers harboring mutations in the MAPK/ERK pathway such as melanoma. We have observed significant responses to trametinib in patients with refractory PLGG in our institutions and results from the phase I study are promising. The treatment appears not only efficacious but is also usually well tolerated. We hypothesize that we will observe responses in the majority of refractory PLGG and PN treated with trametinib in this phase 2 study. Methods The primary objective is to determine the objective response rate of trametinib as a single agent for treatment of progressing/refractory tumors with MAPK/ERK pathway activation. The TRAM-01 study is a phase II multicentric open-label basket trial including four groups. Group 1 includes NF1 patients with progressing/refractory glioma. Group 2 includes NF1 patients with plexiform neurofibroma. Group 3 includes patients with progressing/refractory glioma with KIAA1549-BRAF fusion. Group 4 includes other patients with progressing/refractory glioma with activation of the MAPK/ERK pathway. Eligible patients for a given study group will receive daily oral trametinib at full dose for a total of 18 cycles of 28 days. A total of 150 patients will be enrolled in seven Canadian centers. Secondary objectives include the assessment of progression-free survival, overall survival, safety and tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment. Discussion Trametinib will allow us to target directly and specifically the MAPK/ERK pathway. We expect to observe a significant response in most patients. Following our study, trametinib could be integrated into standard treatment of PLGG and PN. Trial registration ClinicalTrials.gov Identifier: NCT03363217 December 6, 2017.

The MEK inhibitor selumetinib induces objective responses and provides clinical benefit in children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PNs). To evaluate whether similar outcomes were possible in adult patients, in whom PN growth is generally slower than in pediatric patients, we conducted an open-label phase 2 study of selumetinib in adults with NF1 PNs. The study was designed to evaluate objective response rate (primary objective), tumor volumetric responses, patient-reported outcomes and pharmacodynamic effects in PN biopsies. The objective response rate was 63.6% (21/33 participants). Median maximal PN volume decrease was 23.6% (range: −48.1% to 5.5%). No disease progression relative to baseline PN volumes occurred before data cutoff, with a median of 28 cycles completed (range: 1–78, 28 d per cycle). Participants experienced decreased tumor pain intensity and pain interference. Adverse events (AEs) were similar to those of the pediatric trial; acneiform rash was the most prevalent AE. Phosphorylation ratios of ERK1/2 decreased significantly (ERK1 median change: −64.6% (range: −99.5% to 90.7%), ERK2 median change: −57.3% (range: −99.9% to 84.4%)) in paired PN biopsies ( P  ≤ 0.001 for both isoforms) without compensatory phosphorylation of AKT1/2/3. The sustained PN volume decreases, associated improvement in pain and manageable AE profile indicate that selumetinib provides benefit to adults with NF1 and inoperable PNs. ClinicalTrials.gov identifier: NCT02407405 . In a phase 2 trial of adults with neurofibromatosis type 1 and inoperable/growing plexiform neurofibromas, treatment with the MEK inhibitor selumetinib resulted in an objective response rate of 63.6% and improvement in other patient outcomes, with additional biopsy-based data providing further information on drug activity.

Plexiform neurofibromas are slow-growing chemoradiotherapy-resistant tumours arising in patients with neurofibromatosis type 1 (NF1). Currently, there are no viable therapeutic options for patients with plexiform neurofibromas that cannot be surgically removed because of their proximity to vital body structures. We undertook an open-label phase 2 trial to test whether treatment with imatinib mesylate can decrease the volume burden of clinically significant plexiform neurofibromas in patients with NF1. Eligible patients had to be aged 3–65 years, and to have NF1 and a clinically significant plexiform neurofibroma. Patients were treated with daily oral imatinib mesylate at 220 mg/m2 twice a day for children and 400 mg twice a day for adults for 6 months. The primary endpoint was a 20% or more reduction in plexiform size by sequential volumetric MRI imaging. Clinical data were analysed on an intention-to-treat basis; a secondary analysis was also done for those patients able to take imatinib mesylate for 6 months. This trial is registered with ClinicalTrials.gov, number NCT01673009. Six of 36 patients (17%, 95% CI 6–33), enrolled on an intention-to-treat basis, had an objective response to imatinib mesylate, with a 20% or more decrease in tumour volume. Of the 23 patients who received imatinib mesylate for at least 6 months, six (26%, 95% CI 10–48) had a 20% or more decrease in volume of one or more plexiform tumours. The most common adverse events were skin rash (five patients) and oedema with weight gain (six). More serious adverse events included reversible grade 3 neutropenia (two), grade 4 hyperglycaemia (one), and grade 4 increases in aminotransferase concentrations (one). Imatinib mesylate could be used to treat plexiform neurofibromas in patients with NF1. A multi-institutional clinical trial is warranted to confirm these results. Novartis Pharmaceuticals, the Indiana University Simon Cancer Centre, and the Indiana University Herman B Wells Center for Pediatric Research.

PurposeSelumetinib is an FDA-approved targeted therapy for plexiform neurofibromas in neurofibromatosis type 1(NF1) with durable response rates seen in most, but not all patients. In this proof-of-concept study, we demonstrate single-cell RNA sequencing(scRNAseq) as a technique for quantifying drug response to selumetinib at the single cell level.MethodsscRNAseq data from neurofibroma biopsies was obtained from a public genomics repository. Schwann cell populations were identified through standard clustering techniques and single-cell selumetinib sensitivity was quantified on a scale of 0(resistant) to 1(sensitive) based on the expression pattern of a 500 gene selumetinib sensitivity signature from the BeyondCell sensitivity library.ResultsA total of seven plexiform neurofibromas were included in our final analysis. The median absolute number of Schwann cells across samples was 658 cells (IQR: 1,029 cells, Q1-Q3: 135 cells to 1,163 cells). There was a statistically significant difference in selumetinib sensitivity profiles across samples (p < 0.001). The tumor with the highest median selumetinib sensitivity score had a median selumetinib sensitivity score of 0.64(IQR: 0.14, Q1-Q3: 0.59–0.70, n = 112 cells) and the tumor with the lowest median selumetinib sensitivity score had a median score of 0.37 (IQR: 0.21, Q1-Q3: 0.27–0.48, n = 1,034 cells).ConclusionsscRNAseq of plexiform neurofibroma biopsies reveals differential susceptibilities to selumetinib on a single cell level. These findings may explain the partial responses seen in clinical trials of selumetinib for NF1 and demonstrate the value of collecting scRNAseq data for future NF1 trials.

Neurofibromatosis type 1 (NF1), the most common tumor predisposition syndrome, occurs when NF1 gene variants result in loss of neurofibromin, a negative regulator of RAS activity. Plexiform neurofibromas (PN) are peripheral nerve sheath tumors that develop in patients with NF1 and are associated with substantial morbidity and for which, until recently, the only treatment was surgical resection. However, surgery carries several risks and a proportion of PN are considered inoperable. Understanding the genetic underpinnings of PN led to the investigation of targeted therapies as medical treatment options, and the MEK1/2 inhibitor selumetinib has shown promising efficacy in pediatric patients with NF1 and symptomatic, inoperable PN. In a phase I/II trial, most children (approximately 70%) achieved reduction in tumor volume accompanied by improvements in patient-reported outcomes (decreased tumor-related pain and improvements in quality of life, strength, and range of motion). Selumetinib is currently the only licensed medical therapy indicated for use in pediatric patients with symptomatic, inoperable NF1-PN, with approval based on the results of this pivotal clinical study. Several other MEK inhibitors (binimetinib, mirdametinib, trametinib) and the tyrosine kinase inhibitor cabozantinib are also being investigated as medical therapies for NF1-PN. Careful consideration of multiple aspects of both disease and treatments is vital to reduce morbidity and improve outcomes in patients with this complex and heterogeneous disease, and clinicians should be fully aware of the risks and benefits of available treatments. There is no single treatment pathway for patients with NF1-PN; surgery, watchful waiting, and/or medical treatment are options. Treatment should be individualized based on recommendations from a multidisciplinary team, considering the size and location of PN, effects on adjacent tissues, and patient and family preferences. This review outlines the treatment strategies currently available for patients with NF1-PN and the evidence supporting the use of MEK inhibitors, and discusses key considerations in clinical decision-making.

Plexiform neurofibroma, a benign peripheral nerve tumor, is associated with the biallelic loss of function of the NF1 tumor suppressor in Schwann cells. Here, we show that FLLL32, a small molecule inhibitor of JAK2/STAT3 signaling, reduces neurofibroma growth in mice with conditional, biallelic deletion of Nf1 in the Schwann cell lineage. FLLL32 treatment or Stat3 deletion in tumor cells reduced inflammatory cytokine expression and tumor macrophage numbers in neurofibroma. Although STAT3 inhibition downregulated the chemokines CCL2 and CCL12, which can signal through CCR2 to recruit macrophages to peripheral nerves, deletion of Ccr2 did not improve survival or reduce macrophage numbers in neurofibroma-bearing mice. Interestingly, Iba1+; F4/80+;CD11b+ macrophages accounted for ~20–40% of proliferating cells in untreated tumors. FLLL32 suppressed macrophage proliferation, implicating STAT3-dependent, local proliferation in neurofibroma macrophage accumulation, and decreased Schwann cell proliferation and increased Schwann cell death. The functions of STAT3 signaling in neurofibroma Schwann cells and macrophages, and its relevance as a therapeutic target in neurofibroma, merit further investigation.

Neurofibromatosis type 1 (NF1) is a hereditary tumour syndrome that predisposes to benign and malignant tumours originating from neural crest cells. Biallelic inactivation of the tumour-suppressor gene NF1 in glial cells in the skin, along a nerve plexus or in the brain results in the development of benign tumours: cutaneous neurofibroma, plexiform neurofibroma and glioma, respectively. Despite more than 40 years of research, only one medication was recently approved for treatment of plexiform neurofibroma and no drugs have been specifically approved for the management of other tumours. Work carried out over the past several years indicates that inhibiting different cellular signalling pathways (such as Hippo, Janus kinase/signal transducer and activator of transcription, mitogen-activated protein kinase and those mediated by sex hormones) in tumour cells or targeting cells in the microenvironment (nerve cells, macrophages, mast cells and T cells) might benefit NF1 patients. In this review, we outline previous strategies aimed at targeting these signalling pathways or cells in the microenvironment, agents that are currently in clinical trials, and the latest advances in basic research that could culminate in the development of novel therapeutics for patients with NF1.