International Research Journal of Oncology

Advancing Neurofibromatosis Type 1 Therapies through Basic Research Translation

Jude Oluwapelumi Alao *

Microbiology Department, Adeleke University, Ede, Osun State, Nigeria.

Oluwaseyi Joy Alao

Herefordshire and Worchestershire Health and Care NHS Trust, UK.

Zainab Precious Adebayo

Microbiology Department, Adeleke University, Ede, Osun State, Nigeria.

*Author to whom correspondence should be addressed.

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Abstract

Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by the growth of both benign and malignant tumors in neural crest cells. Despite extensive research, only one medication has been approved for plexiform neurofibroma treatment, and no specific drugs exist for other associated tumors. Recent studies suggest targeting cellular signaling pathways (Hippo, Janus kinase/signal transducer and activator of transcription, and mitogen-activated protein kinase) and the microenvironment (nerve cells, macrophages, mast cells, and T cells) as potential therapeutic approaches. Several clinical trials are investigating agents that inhibit specific kinases or target signaling molecules in the microenvironment. Despite significant progress, more effective treatments are needed. This paper reviews previous strategies, ongoing clinical trials, and recent advances in basic research related to NF1 and its associated tumor. Data collected from scientific databases and literature highlight the potential of novel therapeutics, including kinase inhibitors, signaling molecule modulators, and microenvironment-targeting drugs. Understanding the underlying mechanisms of tumor development and progression in NF1 is crucial for developing effective therapies. This review provides insights into current strategies, ongoing trials, and recent basic research, aiming to improve treatment outcomes and address unmet needs in NF1 management. By bridging the gap between basic research and clinical translation, this work paves the way for advancing NF1 therapies and bringing novel treatments to patients.

Keywords: NF1, tumor, signaling, therapies, cell

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References

Maertens O, Johnson B, Hollstein P, et al. Elucidating distinct roles for NF1 in melanomagenesis. Cancer Discovery. 2013;3(3):338-349. DOI: 10.1158/2159-8290.

Canale DJ, Bebin J. von Recklinghausen disease of the nervous system. In: Vinken PJ, Bruyn GW, eds. Handbook of Clinical Neurology. Vol 14. Holland Publishing Company; 1972:132-162.

Broca P. Sur un cas de dégénérescence musculaire progressive avec anomalies de la peau et des os sous-cutanés [A case of progressive muscular degeneration with anomalies of the skin and subcutaneous bones]. Bull Soc Anat Paris. 1886;61:123-126.

Pack GT. Heredity in Neuro-Fibromatosis (von Recklinghausen's Disease). Am J Med Sci. 1910;140(3):359-366.

Roach ES, Gorsky M. Neurofibromatosis 1: Clinical findings in 111 patients. Neurology. 1987;37(1):121-127.

Weinberg JM, Aylsworth AS, Carey JC, et al. The neurofibromatoses: A review of the clinical and genetic aspects of neurofibromatosis 1 and neurofibromatosis 2. J Pediatr. 1987;111(2):181-189.

International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature. 2003;409(6822):860-921.

Chaivorapol C, Garg S, Gutmann DH. NF1 microdeletions: Clinical and molecular characterization. Am J Med Genet Part A. 2017;173(12):3234-3242.

Adil A, Koritala T, Munakomi S. Neurofibromatosis Type 1. In: StatPearls [Internet]. StatPearls Publishing; 2022.

Available:https://www.ncbi.nlm.nih.gov/books/NBK459358/

Ferner RE, Huson SM, Thomas N, et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet. 2007;44(2):81-88.

DOI: 10.1136/jmg.2006.045906.

Gutmann DH, Aylsworth A, Carey JC, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA. 1997;278(1):51-57.

Dombi E, Solomon J, Gillespie AJ, et al.,. NF1 plexiform neurofibroma growth rate by volumetric MRI: Relationship to age and body weight. Neurology. 2007;68(9):643-647.

DOI:10.1212/01.wnl.0000250332.89420.e6

Wolkenstein P, Zeller J, Revuz J, et al. Quality-of-life impairment in neurofibromatosis type 1: A cross-sectional study of 128 cases. Arch Dermatol. 2001;137(11):1421-1425.

Ferner RE. Neurofibromatosis 1 and neurofibromatosis 2: A twenty-first century perspective. Lancet Neurol. 2007;6(4):340-351. DOI:10.1016/S1474-4422(07)70075-3.

Upadhyaya M, Huson SM, Davies M, et al. An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): Evidence of a clinically significant NF1 genotype-phenotype correlation. Am J Hum Genet. 2007;80(1):140-151.

DOI:10.1086/510781

Ferner RE, Gutmann DH. International consensus statement on malignant peripheral nerve sheath tumors in neurofibromatosis. Cancer Res. 2002; 62(5):1573-1577.

Zudek J, Birch P, Riccardi VM, Evans DG, et al. Associations of clinical features in neurofibromatosis 1 (NF1). Genet Epidemiol. 2000;19(4):429-439.

DOI:10.1002/1098-2272(200012)19:4<429:AID-GEPI1>3.0.CO;2-A

Gerber PA, Antal AS, Neumann NJ, et al. Neurofibromatosis. Eur J Med Res. 2009;14(3):102-105.

DOI: 10.1186/2047-783X-14-3-102.

Brosseau JP, Liao CP, Le LQ. Translating current basic research into future therapies for neurofibromatosis type 1. Br J Cancer. 2020;122(2):178-186.

DOI: 10.1038/s41416-020-0903-x

Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004;101(36):13306-13311.

Yap TA, Vidal L, Adam J, et al. Phase I trial of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients with advanced solid tumors. J Clin Oncol. 2010;28(25):3965-3972.

Ritter CA, Perez-Torres M, Rinehart C, et al. Human breast cancer cells selected for resistance to trastuzumab in vivo overexpress epidermal growth factor receptor and ErbB ligands and remain dependent on the ErbB receptor network. Clin Cancer Res. 2007;15,13(16):4909-19. DOI: 10.1158/1078-0432.CCR-07-0701.

Liang W, Guan KL. MAPK and mTOR signaling pathways converge on eIF4B to control its phosphorylation and activity. EMBO J. 2021;40(3):e105142.

DOI: 10.15252/embj.2020105142

Al-Lazikani B, Banerji U, Workman P. Combinatorial drug therapy for cancer in the post-genomic era. Nat Biotechnol. 2012;30(7):679-692.

DOI: 10.1038/nbt.2284

Nakanishi Y, Akiyama N, Tsukaguchi T, et al. Mechanism of Oncogenic Signal Activation by the Novel Fusion Kinase FGFR3-BAIAP2L1. Mol Cancer Ther. 2015;14(3):704-12.

DOI: 10.1158/1535-7163.

Philpott C, Tovell H, Frayling IM, et al. The NF1 somatic mutational landscape in sporadic human cancers. Hum Genomics. 2017;11(1):13.

DOI: 10.1186/s40246-017-0109-3

Weiss B, Widemann BC, Wolters P et al. Sirolimus for progressive neurofibromatosis type 1-associated plexiform neurofibromas: a neurofibromatosis Clinical Trials Consortium phase II study. Neuro Oncol. 2015;17(4):596-603.

DOI: 10.1093/neuonc/nou235.

Epub 2014 Oct 14. Erratum in: Neuro Oncol. 2015;17(6):905.

Mao B, Zhang Q, Ma L, et al. Overview of Research into mTOR Inhibitors. Molecules. 2022;27(16):5295.

DOI: 10.3390/molecules27165295.

Dombi E, Baldwin A, Marcus LJ, et al. Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas. N Engl J Med. 2016, 29;375(26):2550-2560.

DOI: 10.1056/NEJMoa1605943.

Kondyli M, Larouche V, Saint-Martin C, et al. Trametinib for progressive pediatric low-grade gliomas. J Neurooncol. 2018;140: 435-444.

DOI: 10.1007/s11060-018-2994-y.

Malone CF, Fromm JA, Maertens O, et al. Defining key signaling nodes and therapeutic biomarkers in NF1-mutant cancers. Cancer Discov. 2014;4:1062-1073.

DOI: 10.1158/2159-8290.CD-14-0349.

Shurell E, Singh AS, Crompton JG, et al. Characterizing the immune microenvironment of malignant peripheral nerve sheath tumor by PD-L1 expression and presence of CD8+ tumor infiltrating lymphocytes. Oncotarget. 2016;7(39):64300-64308.

DOI: 10.18632/oncotarget.11734.

Fletcher JS, Wu J, Jessen WJ et al. Cxcr3-expressing leukocytes are necessary for neurofibroma formation in mice. JCI Insight. 2019;4(3):e98601.

DOI: 10.1172/jci.insight.98601.

Havel JJ, Chowell D, Chan TA. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat Rev Cancer. 2019;19:133-150.

DOI: 10.1038/s41568-019-0116-x

Pan Y, Xiong M, Chen R, et al. Athymic mice reveal a requirement for T-cell-microglia interactions in establishing a microenvironment supportive of Nf1 low-grade glioma growth. Genes Dev. 2018;32:491-496.

DOI: 10.1101/gad.310625.118

Patel AJ, Liao CP, Chen Z, et al. BET bromodomain inhibition triggers apoptosis of NF1-associated malignant peripheral nerve sheath tumors through Bim induction. Cell Rep. 2014;6:81-92.

DOI: 10.1016/j.celrep.2013.11.028

Wu J, Keng VW, Patmore DM, et al. Insertional mutagenesis identifies a STAT3/Arid1b/β-catenin pathway driving neurofibroma initiation. Cell Rep. 2016;14:1979-1990. DOI:10.1016/j.celrep.2016.01.074

Kim YS, Shin S, Jung SH, et al. Pathogenic NF1 truncating mutation and copy number alterations in a dedifferentiated liposarcoma with multiple lung metastasis: a case report. BMC Med Genet. 2020;21(1):200.

DOI: 10.1186/s12881-020-01137-4

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): 277-286.

DOI: 10.1038/s41434-019-0080-9

Lehmann HC, Höke A. Schwann cells as a therapeutic target for peripheral neuropathies. CNS Neurol Disord Drug Targets. 2010;9(6):801-6.

DOI: 10.2174/187152710793237412

Aboul-Soud MA, Alzahrani AJ, Mahmoud A. Induced Pluripotent Stem Cells (iPSCs)-Roles in Regenerative Therapies, Disease Modelling and Drug Screening. Cells. 2021;10(9):2319.

DOI: 10.3390/cells10092319

Patritti Cram J, Wu J, Coover RA, et al. P2RY14 cAMP signaling regulates Schwann cell precursor self-renewal, proliferation, and nerve tumor initiation in a mouse model of neurofibromatosis. Elife. 2022;11:e73511.

DOI: 10.7554/eLife.73511

Cooney DS, Wimmers EG, Ibrahim Z, et al. Mesenchymal Stem Cells Enhance Nerve Regeneration in a Rat Sciatic Nerve Repair and Hindlimb Transplant Model. Sci Rep. 2016;6:31306.

DOI: 10.1038/srep31306

Jung M, Pfeifer GP. CRISPR/Cas9 editing of the NF1 gene to characterize the functional significance of missense mutations found in human melanoma. Genes Chromosomes Cancer. 2018;57(5): 238-246.

DOI: 10.1002/gcc.22534

Moutal A, Yang X, Li W, et al. CRISPR/Cas9 editing of Nf1 gene identifies CRMP2 as a therapeutic target in neurofibromatosis type 1-related pain that is reversed by (S)-Lacosamide. Pain. 2017;158(12):2301-2319.

DOI: 10.1097/j.pain.0000000000001002

Zhang H, Chen Z, Wang X, et al. Long non-coding RNA: a new player in cancer. J Hematol Oncol. 2013;6:37.

DOI: 10.1186/1756-8722-6-37

Teplyuk NM, Uhlmann EJ, Gabriely G, et al. Therapeutic potential of targeting microRNA-10b in established intracranial glioblastoma: first steps toward the clinic. EMBO Mol Med. 2016;8(3):268-87.

DOI: 10.15252/emmm.201505495

Daginakatte GC, Gutmann DH. Neurofibromatosis-1 (Nf1) heterozygous brain microglia elaborate paracrine factors that promote Nf1-deficient astrocyte and glioma growth. Hum Mol Genet. 2007;16: 1098-1112.

Solga AC, Pong WW, Kim KY, et al. RNA sequencing of tumor-associated microglia reveals Ccl5 as a stromal chemokine critical for neurofibromatosis-1 glioma growth. Neoplasia. 2015;17:776-788.

Prada CE, Jousma E, Rizvi TA, et al. Neurofibroma-associated macrophages play roles in tumor growth and response to pharmacological inhibition. Acta Neuropathol. 2013;125:159-168.

Jakacki RI, Cohen KJ, Buxton A, et al. Phase 2 study of concurrent radiotherapy and temozolomide followed by temozolomide and lomustine in the treatment of children with high-grade glioma: A report of the Children’s Oncology Group ACNS0423 study. Neuro Oncol. 2016;18:1442-1450.