Concomitant Variants in NF1 , LZTR1 , and GNAZ Genes Probably Contribute to the Aggressiveness of Plexiform Neurofibroma and Warrant Treatment with MEK Inhibitor

AbstractPlexiform neurofibromas are congenital peripheral nerve sheath tumors characteristic of neurofibromatosis type 1 (NF1)—a frequent neurocutaneous disorder caused by mutations of the NF1 tumor suppressor gene. Since plexiform neurofibromas are a major cause of the burden of disease and may also progress to malignancy, many efforts have been undertaken to find a cure for these tumors. However, neither surgery nor medication has so far produced a breakthrough therapeutic success. Recently, a clinical phase I study reported significant shrinkage of plexiform neurofibromas following treatment with the MEK inhibitor selumetinib. Here, we report an 11-year-old NF1 patient with a large plexiform neurofibroma of the neck that had led to a sharp-angled kinking of the cervical spine and subsequent myelopathy. Although surgical stabilization of the cervical vertebral column was urgently recommended, the vertebral column was inaccessible due to extensive tumor growth. In this situation, treatment with the MEK inhibitor trametinib was initiated which resulted in a 22% reduction in tumor volume after 6 months of therapy and finally enabled surgery. These data show that MEK inhibitors may not lead to complete disappearance of NF1-associated plexiform neurofibromas but can be an essential step in a multimodal therapeutic approach for these tumors. The course of our patient suggests that MEK inhibitors are likely to play a significant role in providing a cure for one of the most devastating manifestations of NF1.

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Neurofibromatosis: Molecular Pathogenesis and Natural Compounds as Potential Treatments

Frontiers in Oncology ◽

10.3389/fonc.2021.698192 ◽

2021 ◽

Vol 11 ◽

Author(s):

Anusha Amaravathi ◽

Janet L. Oblinger ◽

D. Bradley Welling ◽

A. Douglas Kinghorn ◽

Long-Sheng Chang

Keyword(s):

Target Identification ◽

Plexiform Neurofibroma ◽

Tumor Biology ◽

Mek Inhibitor ◽

Natural Compounds ◽

Major Advance ◽

Primary Therapy ◽

Limited Success ◽

Fda Approval ◽

Genetics And Genomics

The neurofibromatosis syndromes, including NF1, NF2, and schwannomatosis, are tumor suppressor syndromes characterized by multiple nervous system tumors, particularly Schwann cell neoplasms. NF-related tumors are mainly treated by surgery, and some of them have been treated by but are refractory to conventional chemotherapy. Recent advances in molecular genetics and genomics alongside the development of multiple animal models have provided a better understanding of NF tumor biology and facilitated target identification and therapeutic evaluation. Many targeted therapies have been evaluated in preclinical models and patients with limited success. One major advance is the FDA approval of the MEK inhibitor selumetinib for the treatment of NF1-associated plexiform neurofibroma. Due to their anti-neoplastic, antioxidant, and anti-inflammatory properties, selected natural compounds could be useful as a primary therapy or as an adjuvant therapy prior to or following surgery and/or radiation for patients with tumor predisposition syndromes, as patients often take them as dietary supplements and for health enhancement purposes. Here we review the natural compounds that have been evaluated in NF models. Some have demonstrated potent anti-tumor effects and may become viable treatments in the future.

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Impact of MEK inhibitor therapy on neurocognition in neurofibromatosis type 1

10.1101/2020.12.18.20248334 ◽

2020 ◽

Author(s):

Karin S. Walsh ◽

Pamela L. Wolters ◽

Brigitte C. Widemann ◽

Allison A. del Castillo ◽

Maegan D. Sady ◽

...

Keyword(s):

Visual Learning ◽

Plexiform Neurofibroma ◽

Unmet Need ◽

Mek Inhibitor ◽

Cognitive Intervention ◽

Reliable Change Index ◽

Future Research ◽

Group Level ◽

Chi Square ◽

Patients Âgés

AbstractObjectiveNF1-associated cognitive impairments carry significant life-long morbidity. The lack of targeted biologic treatments remains a significant unmet need. We examine changes in cognition in patients with NF1 in the first 48 weeks of MEK inhibitor (MEKi) treatment.Methods59 NF1 patients ages 5-27 on a MEKi clinical trial treating plexiform neurofibroma underwent pre-treatment and follow-up cognitive assessments over 48-weeks of treatment. Performance tasks (Cogstate) and observer-reported functioning (BRIEF) were primary outcomes. Group-level (paired t-tests) and individual-level analyses (reliable change index; RCI) were used.ResultsAnalysis showed statistically significant improvements on BRIEF compared to baseline (24-week BRI: t(58)=3.03, p=.004, d=0.24; 48-week MCI: t(39)=2.70, p=.01, d=0.27). RCI indicated more patients had clinically significant improvement at 48-weeks than expected by chance (Chi Square=11.95, p=.001, OR=6.3). Group-level analyses indicated stable performance on Cogstate (p>.05). RCI statistics showed high proportions of improved working memory (24-weeks Chi Square=8.36, p=.004, OR=4.6 and 48-weeks Chi Square=9.34, p=.004, OR=5.3) but not visual learning/memory. Patients with baseline impairments on BRIEF were more likely to show significant improvement than non-impaired patients (24-weeks 46% v. 8%; Chi Square=9.54, p=.008, OR=9.22; 48-weeks 63% v. 16%; Chi Square=7.50, p=.02, OR=9.0).InterpretationOur data shows no evidence of neurotoxicity in 48-weeks of treatment with a MEKi and a potential clinical signal supporting future research of MEKi as a cognitive intervention.

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Extensive Pelvic Plexiform Neurofibroma Presenting As Clitoromegaly in a 3-Year-Old Female: Presentation and Management with MEK Inhibitor

Journal of Pediatric Genetics ◽

10.1055/s-0040-1715638 ◽

2020 ◽

Author(s):

Richelle C. Waldner ◽

Marta Rojas-Vasquez ◽

Peter D. Metcalfe ◽

Andrea M. Haqq

Keyword(s):

Kinase Inhibitor ◽

Bladder Wall ◽

Plexiform Neurofibroma ◽

Pelvic Mass ◽

External Genitalia ◽

Neurofibromatosis Type ◽

Mek Inhibitor ◽

Mitogen Activated Protein Kinase ◽

Type I ◽

Mitogen Activated Protein

AbstractPlexiform neurofibroma (PN) involvement of the external genitalia in patients with neurofibromatosis type I (NF1) is a rare cause of nonhormonal clitoromegaly. We present a 3-year-old female with known NF1 who presented with clitoromegaly. She was identified with an extensive pelvic mass involving the bladder wall, perineum, labia, clitoris, rectum, and sacral foramina. A partial cystectomy was performed, and histopathology was consistent with PN. She has been initiated on a mitogen activated protein kinase enzyme kinase inhibitor, trametinib, which has been effective in achieving partial radiographic response of the bladder mass over 5 months. Additionally, she has experienced clinical response to trematinib with resolution of urinary urgency and frequency since initiating treatment.

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NFB-13. TRAMETINIB FOR PLEXIFORM NEUROFIBROMA AND RECURRENT LOW-GRADE GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa222.616 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii420-iii420

Author(s):

Aimee Sato ◽

Nathan Millard ◽

Francisco Perez ◽

Nicholas Vitanza ◽

Sarah Leary

Keyword(s):

Plexiform Neurofibroma ◽

Retrospective Chart Review ◽

Neurofibromatosis Type ◽

Mek Inhibitor ◽

Tumor Location ◽

Low Grade Glioma ◽

Inhibitor Therapy ◽

Driver Mutations ◽

Low Grade ◽

Standard Clinical Practice

Abstract BACKGROUND Based on early clinical efficacy data, Seattle Children’s established a standard clinical practice for MEK inhibitor therapy for children with plexiform neurofibroma (PN) or recurrent low-grade glioma (LGG). METHODS Data were collected under an IRB-approved retrospective chart review. Trametinib was prescribed off-label at 0.025 mg/kg daily for up to two years. Physical exam and laboratory monitoring were monthly for 3 months, then every 3 months. Retinal examination, ECHO/ECG were every 3 months. Tumor response was evaluated by MRI every 3 months for LGG; imaging for PN was dependent on tumor location. RESULTS 30 patients received trametinib; 17 LGG, 16 PN (3 both); 22 with Neurofibromatosis, Type-1 (NF1); 16 female/15 male; median age 11 (range 4.1–22.6). Most common tumor location was optic pathway (n=11) and face/neck (n=10). Most common adverse events (AE) were dermatologic and gastrointestinal. Ten had dose interruption/reduction, only one discontinued therapy for AE. Six received dermatology specialty care for AE. With median follow-up of 12 months, only 3 patients had progression, one with NF1. One-year EFS was 100% for PN and 88%+7 for LGG. Driver mutations were identified in 9 of 10 tumors tested (5 BRAF fusion, 1 BRAFV600E, 1 FGFR1+NF1, 1 FGFR1+PTPN11, 1 NF1). Radiology review of response will be presented. CONCLUSIONS This real-world pediatric cohort supports efficacy and tolerability of MEK inhibitor therapy for short-term control of plexiform neurofibroma and low-grade glioma with and without NF1. Further studies are warranted to evaluate comparative efficacy, combination therapy and duration of therapy.

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