Перспективы лечения нейрофиброматоза 1-го типа

Мустафин Р.Н. Перспективы лечения нейрофиброматоза 1-го типа. Современная Онкология. 2022;24(2):209–215. DOI: 10.26442/18151434.2022.2.201431

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Mustafin RN. Prospects for the treatment of neurofibromatosis type 1: A review. Journal of Modern Oncology. 2022;24(2):209–215. DOI: 10.26442/18151434.2022.2.201431

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Аннотация

Нейрофиброматоз 1-го типа (НФ1) – аутосомно-доминантный наследственный опухолевый синдром, встречающийся с частотой 1:3000 населения. Около 50% случаев болезни – спорадические, в результате вновь возникшей герминативной мутации в гене NF1. Продукт гена – онкосупрессорный белок нейрофибромин, оказывающий негативное регуляторное влияние на систему RAS-RAF-MEK-ERK. Пациенты сохраняют способность к деторождению, и распространенность болезни в человеческой популяции увеличивается. Именно поэтому перспективна разработка быстрых и эффективных методов диагностики мутации NF1 в семьях с НФ1 для проведения вторичной пренатальной профилактики. Мутации в гене NF1 играют роль также в спорадическом канцерогенезе и в развитии резистентности злокачественных опухолей к химиотерапии. Характерными проявлениями НФ1 являются множественные подкожные и кожные нейрофибромы, пигментные пятна на теле, скелетные аномалии, умственная отсталость, опухоли головного мозга и зрительных нервов. Серьезная проблема НФ1 – склонные к озлокачествлению плексиформные нейрофибромы, развивающиеся у 50% больных и часто обезображивающие их внешность или сдавливающие жизненно важные органы. Сложность в лечении связана с вовлечением в патогенез НФ1 иммунной системы, поскольку в нейрофибромах обнаруживается большое количество дегранулирующих тучных клеток. Выбрасываемые при этом цитокины не обеспечивают должного противоопухолевого иммунного ответа, но стимулируют образование новых и рост существующих нейрофибром. В связи с этим одним из методов терапии предложен длительный прием кетотифена. Хирургическое удаление нейрофибром сопряжено с рецидивами и индуцированием роста новых опухолей, поэтому необходим поиск новых способов лечения НФ1. Описана комплексная терапия с применением кетотифена, Лидазы и Аевита для подавления роста нейрофибром при НФ1. Показана эффективность терапии опухолей при НФ1 с помощью АТФ-независимого ингибитора митоген-активируемой протеинкиназы. Однако для его широкого внедрения в клинику необходимы исследования на больших выборках больных, а также доступность лекарства для больных. Перспективна генная терапия, для разработки которой необходимы идентификация типа мутации в гене NF1 у каждого индивида и использование специфических микроРНК.

Ключевые слова: злокачественные новообразования, кетотифен, селуметиниб, лечение, митоген-активируемая протеинкиназа, мутации, нейрофиброматоз 1-го типа, плексиформные нейрофибромы, таргетная терапия

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Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary tumor syndrome with a prevalence of 1:3000 in human population. About 50% of NF1 cases are sporadic due to newly emerging germline mutations in NF1 gene. Protein product of NF1 is a neurofibromin, which inhibits RAS-RAF-MEK-ERK system. The prevalence of NF1 is increasing as patients are fertile. Therefore, it is important to use rapid diagnostic methods for NF1 mutations in NF1 families for prenatal prophylaxis. Mutations in NF1 gene play roles in sporadic carcinogenesis and in development of cancer resistance to chemotherapy. Specific for NF1 are multiple subcutaneous and cutaneous neurofibromas, age spots, skeletal abnormalities, mental retardation, tumors of the brain and optic nerves. Half of patients with NF1 develop plexiform neurofibromas, which disfigure them or compress vital organs. The difficulty in treating NF1 is due to involvement of immune system, since a large number of degranulating mast cells are found in neurofibromas. Mast cells secrete cytokines that don’t provide a proper anti-tumor immune response, but initiate formation and growth of new neurofibromas. Therefore, long-term administration of ketotiphen was proposed for treatment of NF1 patients. Surgical removal of neurofibromas causes relapses and induction of the growth of new tumors; therefore, it is necessary to develop an effective therapy for NF1. The effectiveness of complex therapy of NF1 with use of ketotiphen, Lydase and Aevit, as well as monotherapy with an ATP-independent inhibitor of mitogen-activated protein kinase, has been described. For widespread clinical implementation of these methods, it is necessary to conduct studies on large sample of patients, as well as to make medicines available for patients. Gene therapy may become promising in the treatment of NF1, which requires identification of the type of mutation in NF1 gene in each individual and the use of specific microRNAs.

Keywords: malignant neoplasms, ketotifen, selumetinib, treatment, mitogen-activated protein kinase, mutations, neurofibromatosis type 1, plexiform neurofibromas, targeted therapy

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1. Bai RY, Esposito D, Tam AJ, et al. Feasibility of using NF1-GRD and AAV for gene replacement therapy in NF1-associated tumors. Gene Ther. 2019;26(6):277-86.
DOI:10.1038/s41434-019-0080-9
2. Ratner N, Miller SJ. A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor. Nat Rev Cancer. 2015;15(5):290-301.
3. Ater JL, Xia C, Mazewski CM, et al. Nonrandomized comparison of neurofibromatosis type 1 and non-neurofibromatosis type 1 children who received carboplatin and vincristine for progressive low-grade glioma: A report from the Children’s Oncology Group. Cancer. 2016;122(12):1928-36. DOI:10.1002/cncr.29987
4. Wei CJ, Gu SC, Ren JY, et al. The impact of host immune cells on the development of neurofibromatosis type 1: The abnormal immune system provides an immune microenvironment for tumorigenesis. Neurooncol Adv. 2019;1(1):vdz037.
5. Payne JM, Barton B, Ullrich NJ, et al. Randomized placebo-controlled study of lovastatin in children with neurofibromatosis type 1. Neurology. 2016;87(24):2575-84.
6. Baldo F, Grasso AG, Wiel LC, et al. Selumetinib in the Treatment of Symptomatic Intractable Plexiform Neurofibromas in Neurofibromatosis Type 1: A Prospective Case Series with Emphasis on Side Effects. Paediatr Drugs. 2020;22(4):417-23.
7. Philpott C, Tovell H, Frayling IM, et al. The NF1 somatic mutational landscape in sporadic human cancers. Hum Genomics. 2017;11(1):13.
8. Whittaker SR, Theurillat JP, Allen EV, et al. A genome-scale RNA interference screen implicates NF1 loss in resistance to RAF inhibition. Cancer Discov. 2013;3(3):350-62.
9. De Bruin EC, Cowell C, Warne PH, et al. Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer. Cancer Discov. 2014;4(5):606-19.
10. Krauthammer M, Kong Y, Bacchiocchi A, et al. Exome sequencing identifies recrurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas. Nat Genet. 2015;47(9):996-1002. DOI:10.1038/ng.3361
11. Pearson A, Proszek P, Pascual J, et al. Inactivating NF1 Mutations Are Enriched in Advanced Breast Cancer and Contribute to Endocrine Therapy Resistance. Clin Cancer Res. 2020;26(3):608-22.
12. Su J, Ruan S, Dai S, et al. NF1 regulates apoptosis in ovarian cancer cells by targeting MCL1 via miR-142-5p. Pharmacogenomics. 2019;20(3):155-65.
13. Vedrine SM, Vourc’h P, Tabagh R, et al. A functional Tetranucleotide (AAAT) polymorphism in an Alu element in the NF1 gene is associated with mental retardation. Neurosci Lett. 2011;491(2):118-21. DOI:10.1016/j.neulet.2011.01.019
14. Zhu C, Saberwal G, Lu Y, et al. The interferon consensus sequence-binding protein activates transcription of the gene encoding neurofibromin 1. J Biol Chem. 2004;279(49):50874-85. DOI:10.1074/jbc.M405736200
15. Riccardi VM. Current utilization of mast cell stabilizers for preemptive treatment of NF1 neurofibromas. Neuro Open Journal. 2015;2(2):67-73.
16. Yang FC, Ingram DA, Chen S, et al. Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for Nf1+/- mast cells. J Clin Invest. 2003;112(12):1851-61.
17. Chen S, Burgin S, McDaniel A, et al. Nf1-/- Schwann cell-conditioned medium modulates mast cell degranulation by c-Kit-mediated hyperactivation of phpsphatidylinositol 3-kinase. Am J Pathol. 2010;177(6):3125-32.
18. Karmakar S, Reilly KM. The role of the immune system in neurofibromatosis type 1-associated nervous system tumors. CNS Oncol. 2017;6(1):45-60.
19. Farschtschi S, Park SJ, Sawitzki B, et al. Effector T cell subclasses associate with tumor burden in neurofibromatosis type 1 patients. Cancer Immunol Immunother. 2016;65(9):1113-21.
20. Marjanska A, Kbicka M, Kurylo-Rafinska B, et al. Lymphocyte Subpopulations in Patients With Neurofibromatosis Type 1-associated Optic Pathway Gliomas and Plexiform Neurofibromas. Anticancer Res. 2019;39(11):6389-92.
21. Park SJ, Sawitzki B, Klowe L, et al. Serum biomarkers for neurofibromatosis type 1 and early detection of malignant peripheral nerve-sheath tumors. BMC Med. 2013;11:109. DOI:10.1186/1741-7015-11-109
22. Mashour GA, Driever PH, Hartmann M, et al. Circulating growth factor levels are associated with tumorigenesis in neurofibromatosis type 1. Clin Cancer Res. 2004;10(17):5677-83.
23. Paschou M, Doxakis E. Neurofibromin 1 is a miRNA target in neurons. PLoS One. 2012;7(10):346773. DOI:10.1371/journal.pone.0046773
24. Stark MS, Bonazzi VF, Boyle GM, et al. miR-514a regulates the tumour suppressor NF1 and modulates BRAFi sensitivity in melanoma. Oncotarget. 2015;6(19):17753‑63. DOI:10.18632/oncotarget.3924
25. Wang S, Ma G, Zhu H, et al. miR-107 regulates tumor progression by targeting NF1 in gastric cancer. Sci Rep. 2016;6:36531. DOI:10.1038/srep36531
26. Sun XX, Zhang SS, Dai CY, et al. LuksS-PV-Regulated MicroRNA-125a 3p Promotes THP-1 Macrophages Differentiation and Apoptosis by Down-Regulating NF1 and Bcl-2. Cell Physiol. Biochem. 2017;44(3):1093-105.
27. Guo L, Li B, Yang J, et al. Fibroblast-derived exosomal microRNA-369 potentiates migration and invasion of lung squamous cell carcinoma cells via NF1-mediated MAPK signaling pathway. Int J Mol Med. 2020;46(2):595-608.
28. Chen J, Cui J, Guo X, et al. Increased expression of miR-641 contributes to erlotinib resistance in non-small-cell lung cancer cells by targeting NF1. Cancer Med. 2018;7(4):1394-403. DOI:10.1002/cam4.1326
29. Zhu H, Yang J, Yang S. MicroRNA-103a-3p potentiates chemoresistance to cisplatin in non-small cell lung carcinoma by targeting neurofibromatosis 1. Exp Ther Med. 2020;19(3):1797-805. DOI:10.3892/etm.2020.8418
30. Li S, Li W, Chen G, et al. MiRNA-27a-3p induces temozolomide resistance in gliomas by inhibiting NF1 level. Am J Transl Res. 2020;12(8):4749-56.
31. Lu H, Liu P, Pang Q. MiR-27a-3p/miR-27b-3p Promotes Neurofibromatosis Type 1 via Targeting of NF1. J Mol Neurosci. 2021;71(11):2353-63.
DOI:10.1007/s12031-020-01779-2
32. Walker JA, Upadhyaya M. Emerging therapeutic targeting for neurofibromatosis. Expert Opin Ther Targets. 2018;22(5):419-37.
33. Cui XW, Ren JY, Gu YH, et al. NF1, Neurofibromin and Gene Therapy: Prospects of Next-Generation Therapy. Curr Gene Ther. 2020;20(2):100-8.
DOI:10.2174/1566523220666200806111451
34. Keeling KM, Xue X, Gunn G, Bedwell DM. Therapeutics based on stop codon readthrough. Annu Rev Genomics Hum Genet. 2014;15:371-94.
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Авторы

Р.Н. Мустафин*

ФГБОУ ВО «Башкирский государственный медицинский университет» Минздрава России, Уфа, Россия
*ruji79@mail.ru

________________________________________________

Rustam N. Mustafin*

Bashkir State Medical University, Ufa, Russia
*ruji79@mail.ru

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