Neurofibromatosis (NF) is a group of autosomal dominant disorders that include three subtypes: neurofibromatosis type 1, neurofibromatosis type 2, and Schwann cell tumor disease. These diseases are phenotypically highly variable, with a predominance of neurological tumors, cutaneous lesions, and peripheral nervous system lesions, causing multiple, progressive damage and posing significant treatment difficulties. Current rational management tools include screening of risk groups, early diagnosis, close follow-up, and a framework for multidisciplinary treatment based on the characteristics of the natural course of this disease. In this article, we review the latest research on disease pathogenesis, genetics, clinical manifestations, and therapeutic approaches.
I. Neurofibromatosis type 1 (NF1)
NF1 mainly presents with multiple neurofibromas throughout the body, and some patients may develop plexiform neurofibromas and malignant peripheral nerve sheath tumour (MPNST). Surgery is currently the main treatment for NF1, but plexiform neurofibroma and MPNST lack envelope and are easily invasive, making them difficult to remove completely and prone to recurrence after surgery.
The product of NF1 tumor suppressor gene is neurofibromin, and deletion of neurofibromin can cause abnormal activation of downstream signaling pathways of Ras system, mainly Ras/Raf/MEK/ERK signaling pathway (i.e. MAPK signaling pathway) and PI3K/AKT/mTOR signaling pathway. In a phase II randomized double-blind crossover controlled trial of the Ras inhibitor Tipifarnib et al, a 20% increase in plexiform neurofibroma volume was considered as tumor progression, and its drug treatment failed to effectively prolong the progression of plexiform neurofibroma in NF1 patients. MAPK signaling pathway, MEK inhibitor could significantly reduce the volume of neurofibroma in NF1 model mice, which could effectively inhibit the growth of MPNST tumors in nude mice inoculated with MPNST, and doubled the survival time of MPNST-inoculated mice.
The AKT/mTOR/S6RP signaling pathway plays an important role in the malignant progression of MPNST, and the activation of this signaling pathway is significantly associated with poor prognosis of NF1 patients. mTOR inhibitor significantly reduced the proliferative activity and invasive ability of MPNST cells, and the continuous application of mTOR inhibitor effectively inhibited the growth of inoculated MPNST tumors in animals, but it failed to cause However, it failed to cause a significant reduction in tumor volume, and the tumors continued to progress after drug discontinuation. In addition, in a phase I clinical cohort study of sorafenib, a multi-target inhibitor for tumor microenvironment and angiogenesis, nine pediatric patients with plexiform neurofibroma NF1 were treated with sorafenib for a median dosing time of approximately 7 months, and the drug failed to cause significant reduction in plexiform neurofibroma volume.
Cognitive impairment is a common symptom of NF1, with an incidence of up to 50% or more. It has been shown that the impairment of cognitive function in NF1 patients is related to the dysregulation of Ras/ERK signaling pathway, and animal experiments have shown that Ras inhibitors can effectively improve cognitive function in NF1 model mice. Because statins have the effect of inhibiting Ras signaling, they have been applied to the treatment of cognitive impairment in NF1 patients in related studies. In a phase I clinical cohort study of lovastatin, after 3 months of treatment with lovastatin in 23 pediatric NF1 patients, 39% of patients showed significant improvement in memory function, while in a randomized double-blind controlled trial of simvastatin, 43 pediatric NF1 patients showed no significant improvement in cognitive function after 12 months of drug treatment.
The current application of molecularly targeted drugs for the treatment of NF1, mainly targeting the Ras signaling pathway, has failed to achieve the desired therapeutic effect in clinical drug trials, and the results of animal experiments with MEK inhibitors have laid the foundation for the next clinical trials of drugs. In addition, the treatment of cognitive impairment in NF1 patients is also a hot topic of current research. Although clinical trials of lovastatin have achieved certain results, they still need to be validated by large-scale clinical studies.
II. Neurofibromatosis type 2 (NF2)
The characteristic manifestation of NF2 is bilateral auditory neuroma, and the hearing loss and hypoacusis have a relatively large impact on patients’ daily life, so bilateral auditory neuroma is often the focus of NF2 treatment.
The surgical procedure is an important treatment for NF2, and Odat et al. showed that when the diameter of the auditory neuroma is less than 1.5 cm and the preoperative hearing is good, the hearing preservation rate is 71%; when the tumor diameter is greater than 2 cm, the surgical hearing preservation is difficult. If the hearing loss on one side is small (<1.5 cm in diameter) and the auditory neuroma on the hearing preserved side is small, clinical observation or trial hearing preservation surgery is feasible; if the tumor is larger (>1.5-50 px), hearing preservation surgery is difficult and non-hearing preservation tumor resection is feasible. Slattery et al. concluded that when hearing loss is caused by auditory neuroma, in order to prolong the hearing preservation time, internal auditory canal decompression is feasible without removing tumor tissues, and the average hearing preservation time after surgery is 2.1 years. In addition, it has been shown that after transcranial fossa hearing preservation surgery for NF2 auditory neuroma, more than 50% of patients may experience tumor regrowth in the operative area, with a mean tumor growth-free time of 42.1 months.
Radiotherapy for NF2 auditory neuroma is still controversial, although radiotherapy can reduce the size of tumor and improve the patient’s hearing for a certain period of time, it can increase the chance of malignant transformation of tumor and cause adhesions between tumor tissue and surrounding nerve tissue, resulting in difficulties in future surgical procedures and increased difficulty in preserving neurological functions. When clinical symptoms appear, surgical treatment can be chosen for NF2 associated meningioma and other schwannomatosis.
After bilateral hearing loss, patients with NF2 may choose cochlear implantation for hearing reconstruction when cochlear nerve function is well preserved, or auditory brainstem implant (ABI) if cochlear nerve function is lost. Most ABI patients are able to correctly identify the background sounds of the environment and enhance their lip-reading ability, and some ABI patients have a significant improvement in hearing, with a speech recognition rate of 70% or more.
In a phase II clinical cohort study of the mTOR inhibitor everolimus, the median dosing time of everolimus in nine patients with NF2 was approximately 6 months, and the drug effect failed to significantly improve the patients’ hearing or cause significant reduction in tumor size (≥15% reduction in size). In a clinical cohort study of the EGFR inhibitor erlotinib, the median duration of erlotinib administration in 11 patients with NF2 was 7.9 months, and the drug effect failed to cause significant reduction in tumor volume (≥20% reduction in volume), and the patients’ hearing failed to improve significantly (mean improvement in pure tone audiometry ≥10 dB), but it could delay the progression of In a phase II clinical cohort study of lapatinib, another inhibitor of EGFR [25], the median duration of lapatinib administration in 21 patients with NF2 was 12 months, and 23.5% of patients showed a significant reduction in tumor volume (≥15% reduction in volume) , 30.8% of patients showed varying degrees of hearing improvement (mean improvement of ≥10 dB in pure-tone audiometry or significant improvement in speech recognition), and the median progression-free time for auditory neuromas was approximately 14 months.
In a retrospective clinical cohort study of the VEGF inhibitor bevacizumab, 31 patients with NF2 were treated with bevacizumab for a median duration of 14 months, and 55% of the audioneuromas were significantly reduced in size after drug treatment (volume reduction The median duration of bevacizumab treatment was 14 months. 55% of the patients had a significant reduction in the size of the auditory neuroma (≥20%) and 57% had a significant improvement in hearing (significant improvement in speech recognition). Another retrospective clinical cohort study of bevacizumab analyzed its therapeutic effect on NF2 meningiomas in a total of 48 meningiomas in 15 patients with a median follow-up of 18 months. 29% of meningiomas were significantly reduced in size (≥20% volume reduction) after drug treatment, but the duration was shorter, with a median maintenance time of 3.7 months for volume reduction and a median no The median time to progression was 15 months.
The multi-target inhibitor of PDGFR/Raf, sorafenib, the PDGF/c-KIT inhibitor imatinib, and nilotinib significantly inhibited the proliferative activity of NF2 sheath tumor cells in culture, and the inhibition of tumor cells was more pronounced when nilotinib was combined with the MEK inhibitor, semitinib. /The PI3K/Akt inhibitor AR42 and HSP90 inhibitors significantly inhibited the proliferative activity of NF2 sheath tumor and meningioma cells in culture, and AR42 reduced the volume of inoculated sheath tumors in animals by 42%, while HSP90 inhibitor significantly inhibited the growth of inoculated sheath tumors in animals, but failed to cause significant reduction in tumor volume. The deletion of Merlin in NF2 also resulted in enhanced activity of p21-activated kinases (PAKs), and Licciulli S et al. successfully inhibited the proliferative activity of cultured NF2 sheath tumor cells using the PAKs inhibitor FRAX597 and suppressed the growth of inoculated NF2 sheath tumors in animals. sheath tumor growth.
NF2 tumors have aberrant activation of multiple signaling pathways, and a wide variety of molecularly targeted drugs are currently being investigated for NF2 therapy. Among the various drugs that have been tested in clinical trials, bevacizumab has the best therapeutic effect, and the EGFR inhibitors erlotinib and lapatinib also have some efficacy.
Schwann cell tumor disease
Schwann cell tumor disease is the third subtype of neurofibromatosis and is characterized by multiple Schwann cell tumors throughout the body. Mutations in the SMARCB1 and LZTR1 genes are thought to be responsible for the development of Schwann cell neoplasm. Surgery is the mainstay of treatment for this disease, and the indications for surgery are the same as for disseminated Schwann cell tumors; however, surgical resection may not improve pain symptoms significantly in some patients. Radiotherapy is also an effective treatment for progressive tumors that are inoperable, but carries the risk of causing malignant transformation of the tumor.
Molecularly targeted drugs for the treatment of Schwann cell tumor disease are still in the research stage. Since SMARCB1 can directly inhibit cell cycle protein D1, SMARCB1 deletion can cause an increase in cell cycle protein D1 activity, resulting in enhanced tumor cell proliferation activity. Therefore, for tumors with SMARCB1 mutations, the cyclin D1/Cdk signaling pathway may be an effective molecular therapeutic target. plotkin SR et al. mentioned in the literature that two patients with Schwann cell tumor disease effectively controlled tumor growth and relieved pain and improved function after applying the anti-angiogenic drug bevacizumab.
IV. Summary and outlook
Neurofibromatosis is a group of diseases caused by genetic mutations, which cannot yet be cured at the genetic level by existing medical technologies. The goal of current treatment is to slow down the progression of the disease and improve the quality of life of the patients as much as possible through various therapeutic means. Molecularly targeted therapeutics are currently a hot topic of research, and clinical studies of some drugs (e.g., bevacizumab, etc.) have yielded certain results. With the in-depth research on the molecular pathogenesis of each subtype of neurofibromatosis, it is believed that more and more effective molecular therapeutic targets will be known, and more and more neurofibromatosis patients will benefit from the treatment with molecularly targeted drugs.