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Neuro-oncology Oct 2023Selumetinib shrank inoperable symptomatic plexiform neurofibromas (PN) in children with neurofibromatosis type 1 (NF1) and provided clinical benefit for many in our...
BACKGROUND
Selumetinib shrank inoperable symptomatic plexiform neurofibromas (PN) in children with neurofibromatosis type 1 (NF1) and provided clinical benefit for many in our previously published phase 1/2 clinical trials (SPRINT, NCT01362803). At the data cutoff (DCO) of the prior publications, 65% of participants were still receiving treatment. This report presents up to 5 years of additional safety and efficacy data from these studies.
METHODS
This manuscript includes data from the phase 1 and phase 2, stratum 1 study which included participants with clinically significant PN-related morbidity. Participants received continuous selumetinib dosing (1 cycle = 28 days). Safety and efficacy data through February 27, 2021 are included. PN response assessed by volumetric magnetic resonance imaging analysis: Confirmed partial response (cPR) ≥20% decrease from baseline on 2 consecutive evaluations. Phase 2 participants completed patient-reported outcome measures assessing tumor pain intensity (Numeric Rating Scale-11) and interference of pain in daily life (pain interference index).
RESULTS
For the 74 children (median age 10.3 years; range 3-18.5) enrolled, overall cPR rate was 70% (52/74); median duration of treatment was 57.5 cycles (range 1-100). Responses were generally sustained with 59% (44) lasting ≥ 12 cycles. Tumor pain intensity (n = 19, P = .015) and pain interference (n = 18, P = .0059) showed durable improvement from baseline to 48 cycles. No new safety signals were identified; however, some developed known selumetinib-related adverse events (AEs) for the first time after several years of treatment.
CONCLUSIONS
With up to 5 years of additional selumetinib treatment, most children with NF1-related PN had durable tumor shrinkage and sustained improvement in pain beyond that previously reported at 1 year. No new safety signals were identified; however, ongoing monitoring for known selumetinib-related AEs is needed while treatment continues.
Topics: Child; Humans; Neurofibromatosis 1; Neurofibroma, Plexiform; Benzimidazoles; Pain
PubMed: 37115514
DOI: 10.1093/neuonc/noad086 -
Acta Medica Portuguesa Dec 2023
Topics: Humans; Neurofibroma, Plexiform; Neurofibromatosis 1
PubMed: 37205744
DOI: 10.20344/amp.19477 -
The Keio Journal of Medicine Aug 2023Neurofibromatosis 1 (NF1), also known as von Recklinghausen disease, is one of the most common neurocutaneous genetic disorders. Loss of function of the NF1 gene results...
Neurofibromatosis 1 (NF1), also known as von Recklinghausen disease, is one of the most common neurocutaneous genetic disorders. Loss of function of the NF1 gene results in overactivation of the RAS/MAPK pathway, leading to neurocutaneous manifestations and osseous abnormalities. Because of medical progress, molecular testing for NF1 after genetic counseling is now available in Japan. In addition, revised diagnostic criteria for NF1 were proposed by NF1 experts of an international panel in 2021. Because the overall degree of severity and manifestations in each patient are not predictable, age-specific annual monitoring and patient education by a multidisciplinary team are important for the management of NF1. Although treatment of plexiform neurofibroma has been challenging, selumetinib (an oral selective MEK1/2 inhibitor), which targets a pathway downstream of RAS, was approved in 2022 for use in children with inoperable, symptomatic plexiform neurofibromas in Japan. This article summarizes recent progress in diagnosis, clinical characteristics, and treatment of various manifestations of NF1 and proposes the future direction required to resolve unmet needs in patients with NF1 in Japan.
PubMed: 37635082
DOI: 10.2302/kjm.2023-0013-IR -
The Journal of Investigative Dermatology Aug 2023Neurofibromatosis type 1 is one of the most common genetic disorders of the nervous system and predisposes patients to develop benign and malignant tumors. Cutaneous... (Review)
Review
Neurofibromatosis type 1 is one of the most common genetic disorders of the nervous system and predisposes patients to develop benign and malignant tumors. Cutaneous neurofibromas (cNFs) are NF1-associated benign tumors that affect nearly 100% of patients with NF1. cNFs dramatically reduce patients' QOL owing to their unaesthetic appearance, physical discomfort, and corresponding psychological burden. There is currently no effective drug therapy option, and treatment is restricted to surgical removal. One of the greatest hurdles for cNF management is the variability of clinical expressivity in NF1, resulting in intrapatient and interpatient cNF tumor burden heterogeneity, that is, the variability in the presentation and evolution of these tumors. There is growing evidence that a wide array of factors are involved in the regulation of cNF heterogeneity. Understanding the mechanisms underlying this heterogeneity of cNF at the molecular, cellular, and environmental levels can facilitate the development of innovative and personalized treatment regimens.
Topics: Humans; Neurofibromatosis 1; Quality of Life; Tumor Burden; Neurofibroma; Skin Neoplasms
PubMed: 37318402
DOI: 10.1016/j.jid.2022.12.027 -
Current Oncology Reports Dec 2023Neurofibromatosis type I (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis represent a diverse group of genetic tumor predisposition syndromes with a shared... (Review)
Review
Neurofibromatosis type I (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis represent a diverse group of genetic tumor predisposition syndromes with a shared feature of tumors affecting the peripheral nerve sheaths. PURPOSE OF REVIEW: Many advancements have been made in understanding the biologic underpinnings of these conditions, and in 2016 the first drug was approved by the FDA to treat pediatric symptomatic unresectable plexiform neurofibromas. RECENT FINDINGS: Mek inhibitors have provided a much-needed therapeutic avenue for NF1 patients with unresectable plexiform neurofibromas (PN), both for reduction of tumor bulk and for improvement in symptoms. Selumetinib is the first FDA approved drug for PN, but is only approved for children. Some research suggests that alternative Mek inhibitors and other mixed tyrosine kinase inhibitors may have better efficacy in adults. Vascular endothelial growth factor (VEGF) inhibitor bevacizumab can prolong hearing and delay the need for surgery in NF2 patients with bilateral vestibular schwannomas. This article provides an update regarding considerations and approaches when treating the tumors associated with the neurofibromatoses (NF), including risk and prognosis metrics, clinical trial results, surgical techniques, and radiation therapy recommendations.
Topics: Adult; Humans; Child; Neurofibroma, Plexiform; Vascular Endothelial Growth Factor A; Neurofibromatoses; Neurofibromatosis 1; Peripheral Nervous System Neoplasms; Genetic Predisposition to Disease; Protein Kinase Inhibitors; Mitogen-Activated Protein Kinase Kinases
PubMed: 37906356
DOI: 10.1007/s11912-023-01451-z -
Clinical Cancer Research : An Official... Sep 2023Plexiform neurofibromas (PNF) are peripheral nerve sheath tumors that cause significant morbidity in persons with neurofibromatosis type 1 (NF1), yet treatment options...
PURPOSE
Plexiform neurofibromas (PNF) are peripheral nerve sheath tumors that cause significant morbidity in persons with neurofibromatosis type 1 (NF1), yet treatment options remain limited. To identify novel therapeutic targets for PNF, we applied an integrated multi-omic approach to quantitatively profile kinome enrichment in a mouse model that has predicted therapeutic responses in clinical trials for NF1-associated PNF with high fidelity.
EXPERIMENTAL DESIGN
Utilizing RNA sequencing combined with chemical proteomic profiling of the functionally enriched kinome using multiplexed inhibitor beads coupled with mass spectrometry, we identified molecular signatures predictive of response to CDK4/6 and RAS/MAPK pathway inhibition in PNF. Informed by these results, we evaluated the efficacy of the CDK4/6 inhibitor, abemaciclib, and the ERK1/2 inhibitor, LY3214996, alone and in combination in reducing PNF tumor burden in Nf1flox/flox;PostnCre mice.
RESULTS
Converging signatures of CDK4/6 and RAS/MAPK pathway activation were identified within the transcriptome and kinome that were conserved in both murine and human PNF. We observed robust additivity of the CDK4/6 inhibitor, abemaciclib, in combination with the ERK1/2 inhibitor, LY3214996, in murine and human NF1(Nf1) mutant Schwann cells. Consistent with these findings, the combination of abemaciclib (CDK4/6i) and LY3214996 (ERK1/2i) synergized to suppress molecular signatures of MAPK activation and exhibited enhanced antitumor activity in Nf1flox/flox;PostnCre mice in vivo.
CONCLUSIONS
These findings provide rationale for the clinical translation of CDK4/6 inhibitors alone and in combination with therapies targeting the RAS/MAPK pathway for the treatment of PNF and other peripheral nerve sheath tumors in persons with NF1.
Topics: Humans; Mice; Animals; Neurofibroma, Plexiform; Neurofibromatosis 1; MAP Kinase Signaling System; Proteomics; Nerve Sheath Neoplasms; Protein Kinase Inhibitors; Neurofibroma; Cyclin-Dependent Kinase 4
PubMed: 37406085
DOI: 10.1158/1078-0432.CCR-22-2854 -
Pediatric Clinics of North America Oct 2023Neurofibromatosis type I (NF1) is a common dominantly inherited disorder, and one of the most common of the RASopathies. Most individuals with NF1 develop plexiform... (Review)
Review
Neurofibromatosis type I (NF1) is a common dominantly inherited disorder, and one of the most common of the RASopathies. Most individuals with NF1 develop plexiform neurofibromas and cutaneous neurofibromas, nerve tumors caused by NF1 loss of function in Schwann cells. Cell culture models and mouse models of NF1 are being used to test drug efficacy in preclinical trials, which led to Food and Drug Administration approval for use of MEK inhibitors to shrink most inoperable plexiform neurofibromas. This article details methods used for testing in preclinical models, and outlines newer models that may identify additional, curative, strategies.
Topics: United States; Humans; Animals; Mice; Child; Neurofibromatosis 1; Neurofibroma, Plexiform
PubMed: 37704352
DOI: 10.1016/j.pcl.2023.05.007 -
American Journal of Medical Genetics.... Oct 2023Neurofibromatosis (NF) and schwannomatosis (SWN) are genetic conditions characterized by the risk of developing nervous system tumors. Recently revised diagnostic... (Review)
Review
Neurofibromatosis (NF) and schwannomatosis (SWN) are genetic conditions characterized by the risk of developing nervous system tumors. Recently revised diagnostic criteria include the addition of genetic testing to confirm a pathogenic variant, as well as to detect the presence of mosaicism. Therefore, the use and interpretation of both germline and tumor-based testing have increasing importance in the diagnostic approach, treatment decisions, and risk stratification of these conditions. This focused review discusses approaches to genetic testing of NF- and SWN-related tumor types, which are somewhat rare and perhaps lesser known to non-specialized clinicians. These include gastrointestinal stromal tumors, breast cancer, plexiform neurofibromas with or without transformation to malignant peripheral nerve sheath tumors, gliomas, and schwannomas, and emphasizes the need for inclusion of genetic providers in patient care and appropriate pre- and post-test education, genetic counseling, and focused evaluation by a medical geneticist or other healthcare provider familiar with clinical manifestations of these disorders.
Topics: Humans; Neurofibromatoses; Neurilemmoma; Genetic Testing; Counseling; Neurofibromatosis 1; Neurofibromatosis 2
PubMed: 37485904
DOI: 10.1002/ajmg.a.63346 -
The Journal of Hand Surgery... Oct 2023Plexiform schwannoma is an uncommon benign tumour that grows in a plexiform pattern. We report a 47-year-old man with a mass on the palmar aspect of the...
Plexiform schwannoma is an uncommon benign tumour that grows in a plexiform pattern. We report a 47-year-old man with a mass on the palmar aspect of the metacarpophalangeal joint of the right index finger that had been growing gradually for more than 10 years. The mass was palpated from the distal carpal tunnel to the ulnar aspect of the proximal interphalangeal joint of the index finger, with tingling and numbness sensation. The tumour was a multinodular tumour involving the first common palmar digital nerve to the ulnar proper palmar digital nerve. It was resected and reconstructed with a sural nerve graft. Plexiform schwannoma is rare in the digital nerve, with only six cases reported. Generally, classic schwannomas can be enucleated without causing neurologic deficits; however, plexiform schwannoma may require nerve resection. There have been reports of recurrence of plexiform schwannoma; definitive resection and long-term follow-up are necessary. Level V (Therapeutic).
Topics: Male; Humans; Middle Aged; Neurilemmoma; Paresthesia; Fingers; Neurosurgical Procedures; Wrist
PubMed: 37881820
DOI: 10.1142/S2424835523720190