神经母细胞瘤研究前沿及思考

摘要: 神经母细胞瘤（neuroblastoma，NB）是儿童最常见的颅内实体肿瘤，发现时常常已是晚期，易发生转移，高危NB患儿即使接受高强度治疗，仍可出现复发或转移，治疗效果差。目前NB的发病机制及治疗等已成为儿童实体恶性肿瘤研究的热点、难点。近年来，随着单细胞测序等各种技术手段的进步，NB的发病机制、治疗手段等相关研究取得了诸多进展。本文将对近年来NB的研究进展进行文献综述，阐述了NB的起源、分子遗传学调控机制及免疫学调控机制研究成果，并介绍NB单克隆抗体、肿瘤疫苗、过继细胞疗法及小分子抑制剂的最新进展。
- 神经母细胞瘤 /
- 发病机制 /
- 免疫治疗 /
- 靶向治疗 /
- 研究前沿
Abstract: Neuroblastoma is the most common intracranial solid tumor in children. It is often found at an advanced stage and is prone to metastasis. Even when high-risk patients receive high-intensity treatment, it can still recur or metastasize, and the prognosis is poor. Currently, the pathogenesis and treatment of neuroblastoma have become a research focus and are recognized as difficult issues in the study of pediatric solid tumors. In recent years, with the progress of single-cell sequencing and other techniques, many advances have been made in research on the pathogenesis and management of neuroblastoma. This article reviews the recent progress of research on neuroblastoma, including its origin and molecular, genetic, and immunological regulation mechanisms, and discusses the latest advances in research on monoclonal antibodies, tumor vaccines, adoptive cell therapy, and small-molecule inhibitors of neuroblastoma.
- neuroblastoma /
- pathogenesis /
- immunotherapy /
- targeted therapy /
- research front

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参考文献(37)

[1]	van Groningen T, Koster J, Valentijn LJ, et al. Neuroblastoma is composed of two super-enhancer-associated differentiation states[J]. Nat Genet, 2017, 49(8):1261-1266. doi: 10.1038/ng.3899
[2]	Boeva V, Louis-Brennetot C, Peltier A, et al. Heterogeneity of neuroblastoma cell identity defined by transcriptional circuitries[J]. Nat Genet, 2017, 49(9):1408-1413. doi: 10.1038/ng.3921
[3]	Dong R, Yang R, Zhan Y, et al. Single-cell characterization of malignant phenotypes and developmental trajectories of adrenal neuroblastoma[J]. Cancer Cell, 2020, 38(5):716-733. doi: 10.1016/j.ccell.2020.08.014
[4]	Jansky S, Sharma AK, Korber V, et al. Single-cell transcriptomic analyses provide insights into the developmental origins of neuroblastoma[J]. Nat Genet, 2021, 53(5):683-693.
[5]	Kameneva P, Artemov AV, Kastriti ME, et al. Single-cell transcriptomics of human embryos identifies multiple sympathoblast lineages with potential implications for neuroblastoma origin[J]. Nat Genet, 2021, 53(5):694-706. doi: 10.1038/s41588-021-00818-x
[6]	Guan JK, Hallberg B, Palmer RH. Chromosome imbalances in neuroblastoma-recent molecular insight into chromosome 1p-deletion, 2p-gain, and 11q-deletion identifies new friends and foes for the future[J]. Cancers, 2021, 13(23):5897. doi: 10.3390/cancers13235897
[7]	García-López J, Wallace K, Otero JH, et al. Large 1p36 deletions affecting Arid1a locus facilitate mycn-driven oncogenesis in neuroblastoma[J]. Cell Rep, 2020, 30(2):454-464. doi: 10.1016/j.celrep.2019.12.048
[8]	Lopez G, Conkrite KL, Doepner M, et al. Somatic structural variation targets neurodevelopmental genes and identifies SHANK2 as a tumor suppressor in neuroblastoma[J]. Genome Res, 2020, 30(9):1228-1242.
[9]	Keane S, Améen S, Lindlöf A, et al. Low DLG2 gene expression, a link between 11q-deleted and MYCN-amplified neuroblastoma, causes forced cell cycle progression, and predicts poor patient survival[J]. Cell Commun Signal, 2020, 18(1):65. doi: 10.1186/s12964-020-00553-6
[10]	Siaw JT, Javanmardi N, van den Eynden J, et al. 11q deletion or ALK activity curbs DLG2 expression to maintain an undifferentiated state in neuroblastoma[J]. Cell Rep, 2020, 32(12):108171. doi: 10.1016/j.celrep.2020.108171
[11]	Javanmardi N, Fransson S, Djos A, et al. Analysis of ALK, MYCN, and the ALK ligand ALKAL2 (FAM150B/AUGα) in neuroblastoma patient samples with chromosome arm 2p rearrangements[J]. Genes Chromosomes Cancer, 2020, 59(1):50-57. doi: 10.1002/gcc.22790
[12]	Borenäs M, Umapathy G, Lai WY, et al. ALK ligand ALKAL2 potentiates MYCN-driven neuroblastoma in the absence of ALK mutation[J]. EMBO J, 2021, 40(3):e105784.
[13]	Milosevic J, Treis D, Fransson S, et al. PPM₁D is a therapeutic target in childhood neural tumors[J]. Cancers, 2021, 13(23):6042. doi: 10.3390/cancers13236042
[14]	Rosswog C, Bartenhagen C, Welte A, et al. Chromothripsis followed by circular recombination drives oncogene amplification in human cancer[J]. Nat Genet, 2021, 53(12):1673-1685. doi: 10.1038/s41588-021-00951-7
[15]	Braoudaki M, Hatziagapiou K, Zaravinos A, et al. MYCN in neuroblastoma: “old wine into new wineskins”[J]. Diseases, 2021, 9(4):78.
[16]	Pearson ADJ, Barry E, Mossé YP, et al. Second Paediatric Strategy Forum for anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies: accelerate in collaboration with the European Medicines Agency with the participation of the Food and Drug Administration[J]. Eur J Cancer, 2021, 157:198-213. doi: 10.1016/j.ejca.2021.08.022
[17]	Alaminos M, Davalos V, Cheung NKV, et al. Clustering of gene hypermethylation associated with clinical risk groups in neuroblastoma[J]. J Natl Cancer Inst, 2004, 96(16):1208-1219. doi: 10.1093/jnci/djh224
[18]	Zhu TY, Liu J, Beck S, et al. A pan-tissue DNA methylation atlas enables in silico decomposition of human tissue methylomes at cell-type resolution[J]. Nat Methods, 2022, 19(3):296-306. doi: 10.1038/s41592-022-01412-7
[19]	Phimmachanh M, Han JZR, O'Donnell YEI, et al. Histone deacetylases and histone deacetylase inhibitors in neuroblastoma[J]. Front Cell Dev Biol, 2020, 8:578770.
[20]	Huang L, Zhang XO, Rozen EJ, et al. PRMT5 activates AKT via methylation to promote tumor metastasis[J]. Nat Commun, 2022, 13(1):3955. doi: 10.1038/s41467-022-31645-1
[21]	Pottoo FH, Barkat MA, Harshita, et al. Nanotechnological based miRNA intervention in the therapeutic management of neuroblastoma[J]. Semin Cancer Biol, 2021, 69:100-108. doi: 10.1016/j.semcancer.2019.09.017
[22]	Zhong X, Zhang Y, Wang L, et al. Cellular components in tumor microenvironment of neuroblastoma and the prognostic value[J]. Peer J, 2019, 7:e8017.
[23]	Aiken TJ, Erbe AK, Zebertavage L, et al. Mechanism of effective combination radio-immunotherapy against 9464D-GD2, an immunologically cold murine neuroblastoma[J]. J Immunother Cancer, 2022, 10(5):e004834.
[24]	Pathania AS, Prathipati P, Murakonda SP, et al. Immune checkpoint molecules in neuroblastoma: a clinical perspective[J]. Semin Cancer Biol, 2022, 86(Pt 2):247-258.
[25]	Wienke J, Dierselhuis MP, Tytgat GAM, et al. The immune landscape of neuroblastoma: challenges and opportunities for novel therapeutic strategies in pediatric oncology[J]. Eur J Cancer, 2021, 144:123-150. doi: 10.1016/j.ejca.2020.11.014
[26]	Yu AL, Gilman AL, Ozkaynak MF, et al. Long-term follow-up of a phase III study of ch14.18 (dinutuximab)+cytokine immunotherapy in children with high-risk neuroblastoma: COG study ANBL0032[J]. Clin Cancer Res, 2021, 27(8): 2179-2189.
[27]	Park JA, Cheung NKV. Targets and antibody formats for immunotherapy of neuroblastoma[J]. J Clin Oncol, 2020, 38(16):1836-1848. doi: 10.1200/JCO.19.01410
[28]	Cheung IY, Cheung NKV, Modak S, et al. Survival impact of anti-GD2 antibody response in a phase II ganglioside vaccine trial among patients with high-risk neuroblastoma with prior disease progression[J]. J Clin Oncol, 2021, 39(3):215-226. doi: 10.1200/JCO.20.01892
[29]	Stegantseva MV, Shinkevich VA, Tumar EM, et al. Multi-antigen DNA vaccine delivered by polyethylenimine and Salmonella enterica in neuroblastoma mouse model[J]. Cancer Immunol Immunother, 2020, 69(12):2613-2622. doi: 10.1007/s00262-020-02652-2
[30]	Heitzeneder S, Bosse KR, Zhu Z, et al. GPC2-CAR T cells tuned for low antigen density mediate potent activity against neuroblastoma without toxicity[J]. Cancer Cell, 2022, 40(1):53-69.
[31]	Quamine AE, Olsen MR, Cho MM, et al. Approaches to enhance natural killer cell-based immunotherapy for pediatric solid tumors[J]. Cancers, 2021, 13(11):2796.
[32]	Jonus HC, Burnham RE, Ho A, et al. Dissecting the cellular components of ex vivo γδ T cell expansions to optimize selection of potent cell therapy donors for neuroblastoma immunotherapy trials[J]. Oncoimmunology, 2022, 11(1):2057012. doi: 10.1080/2162402X.2022.2057012
[33]	Pearson AD, Rossig C, MacKall C, et al. Paediatric Strategy Forum for medicinal product development of chimeric antigen receptor T-cells in children and adolescents with cancer: accelerate in collaboration with the European Medicines Agency with participation of the Food and Drug Administration[J]. Eur J Cancer, 2022, 160:112-133. doi: 10.1016/j.ejca.2021.10.016
[34]	DuBois SG, Mosse YP, Fox E, et al. Phase II trial of alisertib in combination with irinotecan and temozolomide for patients with relapsed or refractory neuroblastoma[J]. Clin Cancer Res, 2018, 24(24):6142-6149.
[35]	Moreno L, Barone G, DuBois SG, et al. accelerating drug development for neuroblastoma: summary of the second neuroblastoma drug development strategy forum from innovative therapies for children with cancer and International Society of Paediatric Oncology Europe Neuroblastoma[J]. Eur J Cancer, 2020, 136:52-68. doi: 10.1016/j.ejca.2020.05.010
[36]	Alleboina S, Aljouda N, Miller M, et al. Therapeutically targeting oncogenic CRCs facilitates induced differentiation of NB by RA and the BET bromodomain inhibitor[J]. Mol Ther Oncolytics, 2021, 23:181-191.
[37]	Chen JW, Nelson C, Wong M, et al. Targeted therapy of TERT-rearranged neuroblastoma with BET bromodomain inhibitor and proteasome inhibitor combination therapy[J]. Clin Cancer Res, 2021, 27(5):1438-1451. doi: 10.1158/1078-0432.CCR-20-3044