Trametinib Induces Neurofibroma Shrinkage and Enables Surgery

2019 ◽  
Vol 50 (05) ◽  
pp. 300-303 ◽  
Author(s):  
Pia Vaassen ◽  
Nikola Dürr ◽  
Andreas Röhrig ◽  
Rainer Willing ◽  
Thorsten Rosenbaum
Keyword(s):  
Vertebral Column ◽  
Plexiform Neurofibroma ◽  
Neurofibromatosis Type ◽  
Mek Inhibitor ◽  
Suppressor Gene ◽  
Complete Disappearance ◽  
Therapeutic Success ◽  
Mek Inhibitors ◽  
Plexiform Neurofibromas ◽  
Peripheral Nerve Sheath Tumors

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.

scholarly journals Distinctive epigenomic alterations in NF1-deficient cutaneous and plexiform neurofibromas drive differential MKK/p38 signaling

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jamie L. Grit ◽  
Benjamin K. Johnson ◽  
Patrick S. Dischinger ◽  
Curt J. Essenburg ◽  
Marie Adams ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Transcriptome Profiling ◽  
Neurofibromatosis Type ◽  
Mapk Signaling ◽  
Ras Signaling ◽  
Methylation Array ◽  
Clinical Behavior ◽  
Plexiform Neurofibromas ◽  
Cellular Processes ◽  
Peripheral Nerve Sheath Tumors

AbstractBenign peripheral nerve sheath tumors are the clinical hallmark of Neurofibromatosis Type 1. They account for substantial morbidity and mortality in NF1. Cutaneous (CNF) and plexiform neurofibromas (PNF) share nearly identical histology, but maintain different growth rates and risk of malignant conversion. The reasons for this disparate clinical behavior are not well explained by recent genome or transcriptome profiling studies. We hypothesized that CNFs and PNFs are epigenetically distinct tumor types that exhibit differential signaling due to genome-wide and site-specific methylation events. We interrogated the methylation profiles of 45 CNFs and 17 PNFs from NF1 subjects with the Illumina EPIC 850K methylation array. Based on these profiles, we confirm that CNFs and PNFs are epigenetically distinct tumors with broad differences in higher-order chromatin states and specific methylation events altering genes involved in key biological and cellular processes, such as inflammation, RAS/MAPK signaling, actin cytoskeleton rearrangement, and oxytocin signaling. Based on our identification of two separate DMRs associated with alternative leading exons in MAP2K3, we demonstrate differential RAS/MKK3/p38 signaling between CNFs and PNFs. Epigenetic reinforcement of RAS/MKK/p38 was a defining characteristic of CNFs leading to pro-inflammatory signaling and chromatin conformational changes, whereas PNFs signaled predominantly through RAS/MEK. Tumor size also correlated with specific CpG methylation events. Taken together, these findings confirm that NF1 deficiency influences the epigenetic regulation of RAS signaling fates, accounting for observed differences in CNF and PNF clinical behavior. The extension of these findings is that CNFs may respond differently than PNFs to RAS-targeted therapeutics raising the possibility of targeting p38-mediated inflammation for CNF treatment.

scholarly journals New Model Systems and the Development of Targeted Therapies for the Treatment of Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 477 ◽  
Author(s):  
Kyle B. Williams ◽  
David A. Largaespada
Keyword(s):  
Schwann Cell ◽  
Peripheral Nerve ◽  
Neurofibromatosis Type 1 ◽  
Single Agent ◽  
Neurofibromatosis Type ◽  
Mek Inhibitors ◽  
Nerve Sheath Tumors ◽  
Peripheral Nerve Sheath Tumors ◽  
Nerve Sheath

Neurofibromatosis Type 1 (NF1) is a common genetic disorder and cancer predisposition syndrome (1:3000 births) caused by mutations in the tumor suppressor gene NF1. NF1 encodes neurofibromin, a negative regulator of the Ras signaling pathway. Individuals with NF1 often develop benign tumors of the peripheral nervous system (neurofibromas), originating from the Schwann cell linage, some of which progress further to malignant peripheral nerve sheath tumors (MPNSTs). Treatment options for neurofibromas and MPNSTs are extremely limited, relying largely on surgical resection and cytotoxic chemotherapy. Identification of novel therapeutic targets in both benign neurofibromas and MPNSTs is critical for improved patient outcomes and quality of life. Recent clinical trials conducted in patients with NF1 for the treatment of symptomatic plexiform neurofibromas using inhibitors of the mitogen-activated protein kinase (MEK) have shown very promising results. However, MEK inhibitors do not work in all patients and have significant side effects. In addition, preliminary evidence suggests single agent use of MEK inhibitors for MPNST treatment will fail. Here, we describe the preclinical efforts that led to the identification of MEK inhibitors as promising therapeutics for the treatment of NF1-related neoplasia and possible reasons they lack single agent efficacy in the treatment of MPNSTs. In addition, we describe work to find targets other than MEK for treatment of MPNST. These have come from studies of RAS biochemistry, in vitro drug screening, forward genetic screens for Schwann cell tumors, and synthetic lethal screens in cells with oncogenic RAS gene mutations. Lastly, we discuss new approaches to exploit drug screening and synthetic lethality with NF1 loss of function mutations in human Schwann cells using CRISPR/Cas9 technology.

Oral Manifestations of Neurofibromatosis Type 1 in Children with Facial Plexiform Neurofibroma: Report of Three Cases

2015 ◽  
Vol 39 (2) ◽  
pp. 168-171 ◽  
Author(s):  
KS Cunha ◽  
RE Rozza-de-Menezes ◽  
RM Andrade ◽  
LMS Almeida ◽  
MER Janini ◽  
...  
Keyword(s):  
Trigeminal Nerve ◽  
Neurofibromatosis Type 1 ◽  
Soft Tissues ◽  
Genetic Disorder ◽  
Plexiform Neurofibroma ◽  
Neurofibromatosis Type ◽  
Oral Manifestations ◽  
Plexiform Neurofibromas ◽  
Organ Systems

Neurofibromatosis type 1 (NF1) is a common autosomal genetic disorder with a prevalence of 1 in 3,000 births. NF1 is a complex syndrome characterized by many abnormalities and may affect all organ systems. Oral manifestations of NF1 occur frequently, but reports including NF1 children with facial plexiform neurofibromas and oral alterations are scant. Facial plexiform neurofibroma may cause asymmetry, disfigurement and usually arises from the trigeminal nerve. The aim of this paper is to to report three pediatric NF1 cases with facial plexiform neurofibroma presenting with oral manifestations, which were evaluated clinically and radiographically, and also to briefly review the literature. Patients presented with changes in the oral soft tissues, jaws, and teeth ipsilateral to the tumor.

Radiation-induced rhabdomyosarcoma of the brainstem in a patient with neurofibromatosis Type 2

2010 ◽  
Vol 112 (1) ◽  
pp. 81-87 ◽  
Author(s):  
Matthew L. Carlson ◽  
Dusica Babovic-Vuksanovic ◽  
Ludwine Messiaen ◽  
Bernd W. Scheithauer ◽  
Brian A. Neff ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Stereotactic Radiosurgery ◽  
Tumor Suppressor Gene ◽  
Neurofibromatosis Type ◽  
Suppressor Gene ◽  
Neurofibromatosis Type 2 ◽  
Benign Tumors ◽  
Autosomal Dominant Disorder ◽  
Peripheral Nerve Sheath Tumors

Neurofibromatosis Type 2 (NF2) is a rare autosomal dominant disorder characterized by the development of benign tumors of the peripheral nervous system and the CNS, including schwannomas, meningiomas, and ependymomas. The gene responsible for the development of NF2 acts as a tumor suppressor gene. Stereotactic radiotherapy (SRT) or single-fraction stereotactic radiosurgery has been increasingly used in the past decades to treat benign tumors in patients with NF2. These radiotherapy methods are less invasive and can be potentially used to treat multiple tumors in a single session. The risk of inducing malignancy is unclear. Few reports exist of malignant peripheral nerve sheath tumors, meningiomas, or ependymomas occurring after SRT or stereotactic radiosurgery in patients with NF2. The authors present the first documented case of rhabdomyosarcoma following SRT for multiple NF2-associated schwannomas. Compared with patients with sporadic tumors, NF2 patients having a germline tumor suppressor gene defect may be more prone to secondary malignancies after treatment involving radiation therapy.

scholarly journals LGG-27. TARGETED THERAPY FOR PEDIATRIC LOW-GRADE GLIOMAS AND PLEXIFORM NEUROFIBROMAS WITH TRAMETINIB

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii371-iii371
Author(s):  
Tiffany Nguyen ◽  
Kathleen McMahon ◽  
Molly Hemenway ◽  
Jean Mulcahy Levy ◽  
Nicholas Foreman ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Retrospective Chart Review ◽  
Neurofibromatosis Type ◽  
Mek Inhibitor ◽  
Low Grade ◽  
Plexiform Neurofibromas ◽  
Low Grade Gliomas ◽  
Common Location ◽  
Best Response ◽  
The Face

Abstract BACKGROUND Targeted therapy aimed at modulating the RAS/RAF/MEK/ERK pathway is of increasing interest for patients with plexiform neurofibromas and low-grade gliomas. Trametinib is an FDA-approved MEK inhibitor that has little published pediatric experience to date. METHODS A retrospective chart review of patients treated with trametinib for low-grade gliomas (LGG) and/or plexiform neurofibromas (PN) between 2015–2018 was conducted at Children’s Hospital Colorado. Data collected included patient demographics, lesion location, Neurofibromatosis type 1 (NF1) status, best response of PN/LGG to trametinib, duration of trametinib therapy, and reported toxicities at least possibly attributed to trametinib. RESULTS Thirty (57% male; 73% NF1) patients were identified. Sixteen (53%) patients had PN only, 12 (40%) had LGG only, and two (7%) patients had both PN and LGG. The most common LGG location was the optic pathway/hypothalamus (72%). The most common location of PN was the face (63%). Two-thirds (8/12) of patients with LGG had a BRAF alteration or NF1 mutation. The median age at start of trametinib therapy was 9.9 years (range, 2.0 – 18.8 years). The median duration of trametinib therapy was 0.8 years (range 0.1 – 2.9 years). The most commonly reported adverse event was rash. No patients developed retinal toxicity or cardiotoxicity. Only two (7%) patients discontinued for toxicity and one (3%) for progressive disease. CONCLUSIONS Trametinib can be administered without significant toxicity to children with PN or LGG. Clinical benefit is noted in this cohort; however, prospective clinical trials are necessary to characterize efficacy formally.

scholarly journals Distinctive epigenomic alterations in NF1-deficient cutaneous and plexiform neurofibromas drive differential MKK/P38 signaling

2019 ◽  
Author(s):  
Jamie L. Grit ◽  
Benjamin K. Johnson ◽  
Patrick S. Dischinger ◽  
Curt J. Essenburg ◽  
Stacy Campbell ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Trp Channels ◽  
Transcriptome Profiling ◽  
Neurofibromatosis Type ◽  
Mapk Signaling ◽  
Ras Signaling ◽  
Clinical Behavior ◽  
Plexiform Neurofibromas ◽  
Cellular Processes ◽  
Peripheral Nerve Sheath Tumors

ABSTRACTBenign peripheral nerve sheath tumors are the clinical hallmark of Neurofibromatosis Type 1. They account for substantial morbidity in NF1 and are difficult to manage. Cutaneous (CNF) and plexiform neurofibromas (PNF) share identical histology, but maintain different growth rates and risk of malignant conversion. The reasons for their disparate clinical behavior are not well explained on the basis of recent genome or transcriptome profiling studies. We hypothesized that CNFs and PNFs are epigenetically distinct tumor types that exhibit differential signaling due to genome-wide and site-specific methylation events. We interrogated the methylation profiles of 45 CNFs and 17 PNFs (Illumina EPIC 850K) using normal tissue controls from NF1 subjects. Based on these profiles, we confirm that CNFs and PNFs are epigenetically distinct tumors with broad differences in higher order chromatin states, and specific methylation events altering genes involved in key biological and cellular processes such as inflammatory mediator regulation of TRP channels, RAS/MAPK signaling, actin cytoskeleton rearrangement, and oxytocin signaling. Based our identification of 2 separate DMRs associated with alternative leading exons in MAP2K3, we demonstrate differential RAS/MKK3/P38 signaling between CNFs and PNFs. Epigenetic reinforcement of RAS/MKK/P38 was a defining characteristic of CNFs leading to pro-inflammatory signaling and chromatin conformational changes, whereas PNFs signaled predominantly through RAS/ERK. Tumor size also correlated with specific CpG methylation events. Taken together, these findings confirm that epigenetic regulation of RAS signaling fates accounts for observed differences in CNF and PNF clinical behavior. CNFs may also respond differently than PNFs to RAS-targeted therapeutics raising the possibility of targeting P38-mediated inflammation for CNF treatment.

Neurofibromatosis Type 1: Cognitive and Behavioral Phenotype: Diagnosis and Treatment

2010 ◽  
Author(s):  
Maria T. Acosta
Keyword(s):  
Peripheral Nerve ◽  
Neurofibromatosis Type 1 ◽  
Clinical Manifestations ◽  
Neurofibromatosis Type ◽  
Academic Difficulties ◽  
Plexiform Neurofibromas ◽  
Nerve Sheath Tumors ◽  
Peripheral Nerve Sheath Tumors ◽  
Nerve Sheath

Neurofibromatosis type 1 (Nf1) is a neurocutaneous disorder with a prevalence of approximately 1 in 2,500–3,500 individuals (Ferner et al. 2007). The physical manifestations of Nf1, such as café au lait spots, axillary freckling, iris hamartomas (Lisch nodules), osseous lesions (sphenoid wing dysplasia, pseudoarthrosis), and benign as well as malignant neural tumors (neurofibromas, optic gliomas), are well recognized (Castle et al. 2003; Ferner et al. 2007). National Institutes of Health (NIH) criteria are currently used for clinical diagnosis (1988) (Table 31.1). The clinical severity of this disorder is quite variable, and approximately 20% of children with Nf1 will later have considerable physical complications (Castle et al. 2003; Ferner et al. 2007; Williams et al. 2009). Other clinical manifestations are abnormalities of the cardiovascular, gastrointestinal, renal, and endocrine systems, facial and body disfigurement, cognitive deficit, and malignancies of the peripheral nerve sheath and central nervous system. The tumors that occur in Nf1 are dermal and plexiform neurofibromas, optic gliomas, malignant peripheral nerve sheath tumors (MPNSTs), pheochromocytomas, and rhabdomyosarcomas (Castle et al. 2003). Children with Nf1 have an increased risk of developing myeloid disease, particularly juvenile chronic myeloid leukemia. Some 30%–40% of Nf1 patients develop plexiform neurofibromas (Szudek, Evans, and Friedman 2003). Malignant peripheral nerve sheath tumors are present in 5%–10% of cases (Evans et al. 2002), often in preexisting plexiform neurofibromas (Castle et al. 2003). Although many see the predisposition to cancer as the major concern regarding Nf1, some of the more prevalent features are not directly related to tumors (Acosta, Gioia, and Silva 2006). Cognitive dysfunction, academic difficulties, and school failure, occur in 40%–80% (Hyman, Arthur, and North 2006; Krab et al. 2008; North et al. 1997). These complications affect the day-to-day life of these children, and are the largest cause of lifetime morbidity in the pediatric Nf1 population (Acosta et al. 2006). These deficits impact on long-term adaptation to society (Acosta et al. 2006; Barton and North 2007; Krab et al. 2008; Krab et al. 2009).

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

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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