Bevacizumab Therapy of Neurofibromatosis Type 2 Associated Vestibular Schwannoma in Japanese Patients

Fujii, Masazumi; Ichikawa, Masahiro; Iwatate, Kensho; Bakhit, Mudathir; Yamada, Masayuki; Kuromi, Yosuke; Sato, Taku; Sakuma, Jun; Saito, Kiyoshi

doi:10.2176/nmc.oa.2019-0194

Cited by 10 publications

(6 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Primary outcome is volumetric response or hearing response. Recently, the first phase III randomized clinical trial using bevacizumab was conducted in Japan [ 103 ].…”

Section: Neurofibromatosis Typementioning

confidence: 99%

Current Understanding of Neurofibromatosis Type 1, 2, and Schwannomatosis

Tamura

2021

IJMS

142

View full text Add to dashboard Cite

Neurofibromatosis (NF) is a neurocutaneous syndrome characterized by the development of tumors of the central or peripheral nervous system including the brain, spinal cord, organs, skin, and bones. There are three types of NF: NF1 accounting for 96% of all cases, NF2 in 3%, and schwannomatosis (SWN) in <1%. The NF1 gene is located on chromosome 17q11.2, which encodes for a tumor suppressor protein, neurofibromin, that functions as a negative regulator of Ras/MAPK and PI3K/mTOR signaling pathways. The NF2 gene is identified on chromosome 22q12, which encodes for merlin, a tumor suppressor protein related to ezrin-radixin-moesin that modulates the activity of PI3K/AKT, Raf/MEK/ERK, and mTOR signaling pathways. In contrast, molecular insights on the different forms of SWN remain unclear. Inactivating mutations in the tumor suppressor genes SMARCB1 and LZTR1 are considered responsible for a majority of cases. Recently, treatment strategies to target specific genetic or molecular events involved in their tumorigenesis are developed. This study discusses molecular pathways and related targeted therapies for NF1, NF2, and SWN and reviews recent clinical trials which involve NF patients.

show abstract

“…Primary outcome is volumetric response or hearing response. Recently, the first phase III randomized clinical trial using bevacizumab was conducted in Japan [ 103 ].…”

Section: Neurofibromatosis Typementioning

confidence: 99%

Current Understanding of Neurofibromatosis Type 1, 2, and Schwannomatosis

Tamura

2021

IJMS

142

View full text Add to dashboard Cite

show abstract

“…Goutagny et al reviewed the literature and reported that bevacizumab improved hearing and tumor shrinkage in more than 50% of progressive VS 44) . A study of bevacizumab administration in NF2-related VS in Japanese patients showed a maximum decrease in tumor volume to baseline occurring three months after receiving four doses of bevacizumab (5 mg/kg in two-week intervals) 45) . However, increasing the bevacizumab dose from 5 mg/kg every two weeks to 10 mg/kg was found to be ineffective 46) .…”

Section: Current Status Of Nf2 Drug Discoverymentioning

confidence: 99%

Current progress in genomics and targeted therapies for neurofibromatosis type 2

Hiruta

Saito²,

Bakhit

et al. 2023

FJMS

Self Cite

View full text Add to dashboard Cite

Neurofibromatosis type 2 (NF2), a multiple neoplasia syndrome, is a manifestation of an impaired expression of the merlin protein, exerting inhibitory effects on cell proliferation signals due to abnormalities of the NF2 gene located on chromosome 22. About half of patients inherit a germline mutation from a parent, and nearly 60% of de novo NF2 patients are estimated to have somatic mosaicism. The development of technical methods to detect NF2 gene mutation, including targeted deep sequencing from multiple tissues, improved the diagnostic rate of mosaic NF2. With improved understanding of genetics and pathogenesis, the diagnostic criteria for NF2 were updated to assist in identifying and diagnosing NF2 at an earlier stage. The understanding of cell signaling pathways interacting with merlin has led to the development of molecular-targeted therapies. Currently, several translational studies are searching for possible therapeutic agents targeting VEGF or VEGF receptors. Bevacizumab, an anti-VEGF monoclonal antibody, is widely used in many clinical trials aiming for hearing improvement or tumor volume control. Currently, a randomized, double-masked trial to assess bevacizumab is underway. In this randomized control trial, 12 other Japanese institutions joined the principal investigators in the clinical trial originating at Fukushima Medical University. In this review, we will be discussing the latest research developments regarding NF2 pathophysiology, including molecular biology, diagnosis, and novel therapeutics.

show abstract

“…In a recent meta-analysis, the median treatment duration was 16 months [ 18 , 19 ]. Recently, the first phase III randomized clinical trial using bevacizumab was conducted in Japan [ 20 , 21 ]. Furthermore, progressive sporadic VS also exhibited significant tumor shrinkage after bevacizumab administration [ 22 ].…”

Section: Protein-kinase-related Pathwaymentioning

confidence: 99%

A Critical Overview of Targeted Therapies for Vestibular Schwannoma

Tamura

Toda

2022

IJMS

View full text Add to dashboard Cite

Vestibular schwannoma (VS) is a benign tumor that originates from Schwann cells in the vestibular component. Surgical treatment for VS has gradually declined over the past few decades, especially for small tumors. Gamma knife radiosurgery has become an accepted treatment for VS, with a high rate of tumor control. For neurofibromatosis type 2 (NF2)-associated VS resistant to radiotherapy, vascular endothelial growth factor (VEGF)-A/VEGF receptor (VEGFR)-targeted therapy (e.g., bevacizumab) may become the first-line therapy. Recently, a clinical trial using a VEGFR1/2 peptide vaccine was also conducted in patients with progressive NF2-associated schwannomas, which was the first immunotherapeutic approach for NF2 patients. Targeted therapies for the gene product of SH3PXD2A-HTRA1 fusion may be effective for sporadic VS. Several protein kinase inhibitors could be supportive to prevent tumor progression because merlin inhibits signaling by tyrosine receptor kinases and the activation of downstream pathways, including the Ras/Raf/MEK/ERK and PI3K/Akt/mTORC1 pathways. Tumor-microenvironment-targeted therapy may be supportive for the mainstays of management. The tumor-associated macrophage is the major component of immunosuppressive cells in schwannomas. Here, we present a critical overview of targeted therapies for VS. Multimodal therapy is required to manage patients with refractory VS.

show abstract

Bevacizumab Therapy of Neurofibromatosis Type 2 Associated Vestibular Schwannoma in Japanese Patients

Cited by 10 publications

References 17 publications

Current Understanding of Neurofibromatosis Type 1, 2, and Schwannomatosis

Current Understanding of Neurofibromatosis Type 1, 2, and Schwannomatosis

Current progress in genomics and targeted therapies for neurofibromatosis type 2

A Critical Overview of Targeted Therapies for Vestibular Schwannoma

Contact Info

Product

Resources

About