Advances in Targeted Therapy for Neurofibromatosis Type 2 (NF2)-Associated Vestibular Schwannomas

Cumpston, Evan C; Rhodes, Steven D.; Yates, Charles W.

doi:10.1007/s11912-023-01388-3

Cited by 5 publications

(6 citation statements)

References 40 publications

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“…Additionally, surgical removal is not possible in multiple situations where tumors commonly arise in patients with neurofibromatosis 2, and radiation treatment may transform or accelerate the growth of NF2-related schwannomas. As a result, neurofibromatosis 2 does not have a curative or long-term therapy [ 31 , 32 ].…”

Section: Neurofibromatosis 1 Andmentioning

confidence: 99%

Neurocutaneous Diseases: Diagnosis, Management, and Treatment

Kioutchoukova,

Foster,

Thakkar

et al. 2024

JCM

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Neurocutaneous disorders, also known as phakomatoses, are congenital and acquired syndromes resulting in simultaneous neurologic and cutaneous involvement. In several of these conditions, the genetic phenomenon is understood, providing a pivotal role in the development of therapeutic options. This review encompasses the discussion of the genetic and clinical involvement of neurocutaneous disorders, and examines clinical management and treatment options. With the current advances in genetics, the role of precision medicine and targeted therapy play a substantial role in addressing the management of these conditions. The interconnectedness between therapeutic options highlights the importance of precision medicine in treating each disorder’s unique molecular pathway. This review provides an extensive synthesis of ongoing and current therapeutics in the management of such clinically unique and challenging conditions.

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Section: Neurofibromatosis 1 Andmentioning

confidence: 99%

Neurocutaneous Diseases: Diagnosis, Management, and Treatment

Kioutchoukova,

Foster,

Thakkar

et al. 2024

JCM

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“…While radiotherapy is an alternative therapeutic option in sporadic VS, it is generally not recommended as an early treatment modality for NF2 patients because of a small possible risk of malignant transformation [ 5 ]. Targeted agents have been used for the medical management of NF2-related VS [ 6 – 8 ]. Bevacizumab treatment is associated with high rates of hearing (70%) and tumor (89%) stability [ 9 – 11 ].…”

Section: Introductionmentioning

confidence: 99%

Imaging as an early biomarker to predict sensitivity to everolimus for progressive NF2-related vestibular schwannoma

Nghiemphu,

Vitte,

Dombi

et al. 2024

J Neurooncol

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Purpose NF2-related schwannomatosis (NF2) is characterized by bilateral vestibular schwannomas (VS) often causing hearing and neurologic deficits, with currently no FDA-approved drug treatment. Pre-clinical studies highlighted the potential of mTORC1 inhibition in delaying schwannoma progression. We conducted a prospective open-label, phase II study of everolimus for progressive VS in NF2 patients and investigated imaging as a potential biomarker predicting effects on growth trajectory. Methods The trial enrolled 12 NF2 patients with progressive VS. Participants received oral everolimus daily for 52 weeks. Brain imaging was obtained quarterly. As primary endpoint, radiographic response (RR) was defined as ≥ 20% decrease in target VS volume. Secondary endpoints included other tumors RR, hearing outcomes, drug safety and quality of life (QOL). Results Eight participants completed the trial and four discontinued the drug early due to significant volumetric VS progression. After 52 weeks of treatment, the median annual VS growth rate decreased from 77.2% at baseline to 29.4%. There was no VS RR and 3 of 8 (37.5%) participants had stable disease. Decreased or unchanged VS volume after 3 months of treatment was predictive of stabilization at 12 months. Seven of eight participants had stable hearing during treatment except one with a decline in word recognition score. Ten of twelve participants reported only minimal changes to their QOL scores. Conclusions Volumetric imaging at 3 months can serve as an early biomarker to predict long-term sensitivity to everolimus treatment. Everolimus may represent a safe treatment option to decrease the growth of NF2-related VS in patients who have stable hearing and neurological condition. TRN: NCT01345136 (April 29, 2011).

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“…Since cranial nerves are often affected, this leads to balance problems, dizziness, headaches, facial weakness, and loss of hearing or sight. There are few pharmacological options for treating NFII 4 , 5 although bevacizumab has recently shown promise 6 . Tumors are surgically resected, leading to nerve damage.…”

Section: Introductionmentioning

confidence: 99%

G6PD and ACSL3 are synthetic lethal partners of NF2 in Schwann cells

Kyrkou,

Valla,

Zhang

et al. 2024

Nat Commun

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Neurofibromatosis Type II (NFII) is a genetic condition caused by loss of the NF2 gene, resulting in activation of the YAP/TAZ pathway and recurrent Schwann cell tumors, as well as meningiomas and ependymomas. Unfortunately, few pharmacological options are available for NFII. Here, we undertake a genome-wide CRISPR/Cas9 screen to search for synthetic-lethal genes that, when inhibited, cause death of NF2 mutant Schwann cells but not NF2 wildtype cells. We identify ACSL3 and G6PD as two synthetic-lethal partners for NF2, both involved in lipid biogenesis and cellular redox. We find that NF2 mutant Schwann cells are more oxidized than control cells, in part due to reduced expression of genes involved in NADPH generation such as ME1. Since G6PD and ME1 redundantly generate cytosolic NADPH, lack of either one is compatible with cell viability, but not down-regulation of both. Since genetic deficiency for G6PD is tolerated in the human population, G6PD could be a good pharmacological target for NFII.

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Advances in Targeted Therapy for Neurofibromatosis Type 2 (NF2)-Associated Vestibular Schwannomas

Cited by 5 publications

References 40 publications

Neurocutaneous Diseases: Diagnosis, Management, and Treatment

Neurocutaneous Diseases: Diagnosis, Management, and Treatment

Imaging as an early biomarker to predict sensitivity to everolimus for progressive NF2-related vestibular schwannoma

G6PD and ACSL3 are synthetic lethal partners of NF2 in Schwann cells

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