Journal articles on the topic 'Neuroblastoma'
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1
Stiborová, Marie, Jitka Poljaková, Tomáš Eckschlager, Rene Kizek, and Eva Frei. "DNA and histone deacetylases as targets for neuroblastoma treatment." Interdisciplinary Toxicology 3, no. 2 (June 1, 2010): 47–52. http://dx.doi.org/10.2478/v10102-010-0010-6.
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DNA and histone deacetylases as targets for neuroblastoma treatmentNeuroblastoma, a tumor of the peripheral sympathetic nervous system, is the most frequent solid extra cranial tumor in children and is a major cause of death from neoplasia in infancy. Still little improvement in therapeutic options has been made, requiring a need for the development of new therapies. In our laboratory, we address still unsettled questions, which of mechanisms of action of DNA-damaging drugs both currently use for treatment of human neuroblastomas (doxorubicin, cis-platin, cyclophosphamide and etoposide) and another anticancer agent decreasing growth of neuroblastomasin vitro, ellipticine, are predominant mechanism(s) responsible for their antitumor action in neuroblastoma cell linesin vitro.Because hypoxia frequently occurs in tumors and strongly correlates with advanced disease and poor outcome caused by chemoresistance, the effects of hypoxia on efficiencies and mechanisms of actions of these drugs in neuroblastomas are also investigated. Since the epigenetic structure of DNA and its lesions play a role in the origin of human neuroblastomas, pharmaceutical manipulation of the epigenome may offer other treatment options also for neuroblastomas. Therefore, the effects of histone deacetylase inhibitors on growth of neuroblastoma and combination of these compounds with doxorubicin, cis-platin, etoposide and ellipticine as well as mechanisms of such effects in human neuroblastona cell linesin vitroare also investigated. Such a study will increase our knowledge to explain the proper function of these drugs on the molecular level, which should be utilized for the development of new therapies for neuroblastomas.
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Wei, Qiang, Zhao Guo, Dong Chen, and Xinjian Jia. "MiR-542-3p suppresses neuroblastoma cell proliferation and invasion by downregulation of KDM1A and ZNF346." Open Life Sciences 15, no. 1 (April 10, 2020): 173–84. http://dx.doi.org/10.1515/biol-2020-0018.
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AbstractNeuroblastoma is one of the most common malignancies in infants and children. MicroRNAs (miRNAs) have been reported as significant regulators that play important roles in neuroblastoma development. This research aimed to analyze the functional mechanism of miR-542-3p in neuroblastoma. Here, we found that miR-542-3p was downregulated and KDM1A as well as ZNF346 were upregulated in neuroblastoma tissues and cells. Both overexpression of miR-542-3p and the knockdown of KDM1A suppressed cell proliferation and invasion in neuroblastomas. Moreover, miR-542-3p reduced the levels of KDM1A and ZNF346 through interaction. Both KDM1A overexpression and ZNF346 upregulation weakened the effect of miR-542-3p on neuroblastoma cells. Besides, miR-542-3p negatively regulated tumor growth in vivo. Our results suggested that miR-542-3p suppressed cell proliferation and invasion by targeting KDM1A and ZNF346 in neuroblastomas, providing a theoretical basis for the treatment of neuroblastoma.
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Ando, Kiyohiro, Yusuke Suenaga, and Takehiko Kamijo. "DNA Ligase 4 Contributes to Cell Proliferation against DNA-PK Inhibition in MYCN-Amplified Neuroblastoma IMR32 Cells." International Journal of Molecular Sciences 24, no. 10 (May 19, 2023): 9012. http://dx.doi.org/10.3390/ijms24109012.
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Identifying the vulnerability of altered DNA repair machinery that displays synthetic lethality with MYCN amplification is a therapeutic rationale in unfavourable neuroblastoma. However, none of the inhibitors for DNA repair proteins are established as standard therapy in neuroblastoma. Here, we investigated whether DNA-PK inhibitor (DNA-PKi) could inhibit the proliferation of spheroids derived from neuroblastomas of MYCN transgenic mice and MYCN-amplified neuroblastoma cell lines. DNA-PKi exhibited an inhibitory effect on the proliferation of MYCN-driven neuroblastoma spheroids, whereas variable sensitivity was observed in those cell lines. Among them, the accelerated proliferation of IMR32 cells was dependent on DNA ligase 4 (LIG4), which comprises the canonical non-homologous end-joining pathway of DNA repair. Notably, LIG4 was identified as one of the worst prognostic factors in patients with MYCN-amplified neuroblastomas. It may play complementary roles in DNA-PK deficiency, suggesting the therapeutic potential of LIG4 inhibition in combination with DNA-PKi for MYCN-amplified neuroblastomas to overcome resistance to multimodal therapy.
4
Koneru, Balakrishna, Ahsan Farooqi, Thinh H. Nguyen, Wan Hsi Chen, Ashly Hindle, Cody Eslinger, Monish Ram Makena, et al. "ALT neuroblastoma chemoresistance due to telomere dysfunction–induced ATM activation is reversible with ATM inhibitor AZD0156." Science Translational Medicine 13, no. 607 (August 18, 2021): eabd5750. http://dx.doi.org/10.1126/scitranslmed.abd5750.
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Cancers overcome replicative immortality by activating either telomerase or an alternative lengthening of telomeres (ALT) mechanism. ALT occurs in ~25% of high-risk neuroblastomas, and progression in patients with ALT neuroblastoma during or after front-line therapy is frequent and often fatal. Temozolomide + irinotecan is commonly used as salvage therapy for neuroblastoma. Patient-derived cell lines and xenografts established from patients with relapsed ALT neuroblastoma demonstrated de novo resistance to temozolomide + irinotecan [SN-38 in vitro, P < 0.05; in vivo mouse event-free survival (EFS), P < 0.0001] vs. telomerase-positive neuroblastomas. We observed that ALT neuroblastoma cells manifested constitutive ataxia-telangiectasia mutated (ATM) activation due to spontaneous telomere dysfunction which was not observed in telomerase-positive neuroblastoma cells. We demonstrated that induction of telomere dysfunction resulted in ATM activation that, in turn, conferred resistance to temozolomide + SN-38 (4.2-fold change in IC50, P < 0.001). ATM knockdown (shRNA) or inhibition using a clinical-stage small-molecule inhibitor (AZD0156) reversed resistance to temozolomide + irinotecan in ALT neuroblastoma cell lines in vitro (P < 0.001) and in four ALT xenografts in vivo (EFS, P < 0.0001). AZD0156 showed modest to no enhancement of temozolomide + irinotecan activity in telomerase-positive neuroblastoma cell lines and xenografts. Ataxia telangiectasia and Rad3 related (ATR) inhibition using AZD6738 did not enhance temozolomide + SN-38 activity in ALT neuroblastoma cells. Thus, ALT neuroblastoma chemotherapy resistance occurs via ATM activation and is reversible with ATM inhibitor AZD0156. Combining AZD0156 with temozolomide + irinotecan warrants clinical testing for neuroblastoma.
5
Moore, H. C., K. M. Wood, M. S. Jackson, M. A. Lastowska, D. Hall, H. Imrie, C. P. F. Redfern, et al. "Histological profile of tumours from MYCN transgenic mice." Journal of Clinical Pathology 61, no. 10 (August 4, 2008): 1098–103. http://dx.doi.org/10.1136/jcp.2007.054627.
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Background:MYCN is the most commonly amplified gene in human neuroblastomas. This proto-oncogene has been overexpressed in a mouse model of the disease in order to explore the role of MYCN in this tumour.Aims:To report the histopathological features of neuroblastomas from MYCN transgenic mice.Methods:27 neuroblastomas from hemizygous transgenic mice and four tumours from homozygous mice were examined histologically; Ki67 and MYCN immunocytochemistry was performed in 24 tumours.Results:Tumours obtained from MYCN transgenic mice resembled human neuroblastomas, displaying many of the features associated with stroma-poor neuroblastoma, including heterogeneity of differentiation (but no overt ganglionic differentiation was seen), low levels of Schwannian stroma and a high mitosis karyorrhexis index. The tumours had a median Ki67 labelling index of 70%; all tumours expressed MYCN with a median labelling index of 68%. The most striking difference between the murine and human neuroblastomas was the presence of tingible body macrophages in the transgenic mouse tumours reflecting high levels of apoptosis. This has not previously been described in human or other murine neuroblastoma models.Conclusions:These studies highlight the histological similarities between tumours from MYCN transgenic mice and human neuroblastomas, and reaffirm their role as a valuable model to study the biology of aggressive human neuroblastoma.
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Secomandi, Eleonora, Amreen Salwa, Chiara Vidoni, Alessandra Ferraresi, Carlo Follo, and Ciro Isidoro. "High Expression of the Lysosomal Protease Cathepsin D Confers Better Prognosis in Neuroblastoma Patients by Contrasting EGF-Induced Neuroblastoma Cell Growth." International Journal of Molecular Sciences 23, no. 9 (April 26, 2022): 4782. http://dx.doi.org/10.3390/ijms23094782.
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Neuroblastoma is a malignant extracranial solid tumor arising from the sympathoadrenal lineage of the neural crest and is often associated with N-MYC amplification. Cathepsin D has been associated with chemoresistance in N-MYC-overexpressing neuroblastomas. Increased EGFR expression also has been associated with the aggressive behavior of neuroblastomas. This work aimed to understand the mechanisms linking EGFR stimulation and cathepsin D expression with neuroblastoma progression and prognosis. Gene correlation analysis in pediatric neuroblastoma patients revealed that individuals bearing a high EGFR transcript level have a good prognosis only when CTSD (the gene coding for the lysosomal protease Cathepsin D, CD) is highly expressed. Low CTSD expression was associated with poor clinical outcome. CTSD expression was negatively correlated with CCNB2, CCNA2, CDK1 and CDK6 genes involved in cell cycle division. We investigated the biochemical pathways downstream to EGFR stimulation in human SH-SY5Y neuroblastoma cells engineered for overexpressing or silencing of CD expression. Cathepsin D overexpression decreased the proliferative potential of neuroblastoma cells through downregulation of the pro-oncogenic MAPK signaling pathway. EGFR stimulation downregulated cathepsin D expression, thus favoring cell cycle division. Our data suggest that chemotherapeutics that inhibit the EGFR pathway, along with stimulators of cathepsin D synthesis and activity, could benefit neuroblastoma prognosis.
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Secomandi, Eleonora, Amreen Salwa, Chiara Vidoni, Alessandra Ferraresi, Carlo Follo, and Ciro Isidoro. "High Expression of the Lysosomal Protease Cathepsin D Confers Better Prognosis in Neuroblastoma Patients by Contrasting EGF-Induced Neuroblastoma Cell Growth." International Journal of Molecular Sciences 23, no. 9 (April 26, 2022): 4782. http://dx.doi.org/10.3390/ijms23094782.
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Neuroblastoma is a malignant extracranial solid tumor arising from the sympathoadrenal lineage of the neural crest and is often associated with N-MYC amplification. Cathepsin D has been associated with chemoresistance in N-MYC-overexpressing neuroblastomas. Increased EGFR expression also has been associated with the aggressive behavior of neuroblastomas. This work aimed to understand the mechanisms linking EGFR stimulation and cathepsin D expression with neuroblastoma progression and prognosis. Gene correlation analysis in pediatric neuroblastoma patients revealed that individuals bearing a high EGFR transcript level have a good prognosis only when CTSD (the gene coding for the lysosomal protease Cathepsin D, CD) is highly expressed. Low CTSD expression was associated with poor clinical outcome. CTSD expression was negatively correlated with CCNB2, CCNA2, CDK1 and CDK6 genes involved in cell cycle division. We investigated the biochemical pathways downstream to EGFR stimulation in human SH-SY5Y neuroblastoma cells engineered for overexpressing or silencing of CD expression. Cathepsin D overexpression decreased the proliferative potential of neuroblastoma cells through downregulation of the pro-oncogenic MAPK signaling pathway. EGFR stimulation downregulated cathepsin D expression, thus favoring cell cycle division. Our data suggest that chemotherapeutics that inhibit the EGFR pathway, along with stimulators of cathepsin D synthesis and activity, could benefit neuroblastoma prognosis.
8
Secomandi, Eleonora, Amreen Salwa, Chiara Vidoni, Alessandra Ferraresi, Carlo Follo, and Ciro Isidoro. "High Expression of the Lysosomal Protease Cathepsin D Confers Better Prognosis in Neuroblastoma Patients by Contrasting EGF-Induced Neuroblastoma Cell Growth." International Journal of Molecular Sciences 23, no. 9 (April 26, 2022): 4782. http://dx.doi.org/10.3390/ijms23094782.
Full textAbstract:
Neuroblastoma is a malignant extracranial solid tumor arising from the sympathoadrenal lineage of the neural crest and is often associated with N-MYC amplification. Cathepsin D has been associated with chemoresistance in N-MYC-overexpressing neuroblastomas. Increased EGFR expression also has been associated with the aggressive behavior of neuroblastomas. This work aimed to understand the mechanisms linking EGFR stimulation and cathepsin D expression with neuroblastoma progression and prognosis. Gene correlation analysis in pediatric neuroblastoma patients revealed that individuals bearing a high EGFR transcript level have a good prognosis only when CTSD (the gene coding for the lysosomal protease Cathepsin D, CD) is highly expressed. Low CTSD expression was associated with poor clinical outcome. CTSD expression was negatively correlated with CCNB2, CCNA2, CDK1 and CDK6 genes involved in cell cycle division. We investigated the biochemical pathways downstream to EGFR stimulation in human SH-SY5Y neuroblastoma cells engineered for overexpressing or silencing of CD expression. Cathepsin D overexpression decreased the proliferative potential of neuroblastoma cells through downregulation of the pro-oncogenic MAPK signaling pathway. EGFR stimulation downregulated cathepsin D expression, thus favoring cell cycle division. Our data suggest that chemotherapeutics that inhibit the EGFR pathway, along with stimulators of cathepsin D synthesis and activity, could benefit neuroblastoma prognosis.
9
Keyel, Michelle E., Kathryn L. Furr, Min H. Kang, and C. Patrick Reynolds. "A Multi-Color Flow Cytometric Assay for Quantifying Dinutuximab Binding to Neuroblastoma Cells in Tumor, Bone Marrow, and Blood." Journal of Clinical Medicine 12, no. 19 (September 27, 2023): 6223. http://dx.doi.org/10.3390/jcm12196223.
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GD2, a disialoganglioside, is present on the surface of most neuroblastomas, as well as on some other cancers, such as melanoma and osteogenic sarcoma. The anti-GD2 antibody ch14.18 (dinutuximab) has an FDA-registered indication for use as maintenance therapy for high-risk neuroblastoma with cytokines and 13-cis-retinoic acid after myeloablative therapy. Recent studies using immunohistochemistry of tumor or tumor cells in marrow have shown that some neuroblastomas are negative for GD2. Dinutuximab and other anti-GD2 antibodies are increasingly used in combination with cytotoxic chemotherapy for treating relapsed neuroblastoma, so it is important to be able to identify patients with tumor cells with low GD2 expression, as such patients may experience toxicity but not benefit from the antibody therapy. As the most common clinical samples available for relapsed neuroblastoma are bone marrow aspirates, we developed a method to quantify dinutuximab binding density and the frequency of neuroblastoma cells positive for the antibody in bone marrow aspirates. Here, we describe a multi-color flow cytometry assay that employs non-GD2 antibodies to identify neuroblastoma cells in a mixed population (tumor, bone marrow, or blood) and an anti-GD2 antibody to quantify both the frequency and density of GD2 expression on neuroblastoma cells.
10
Ramsay, Hans A., Kalevi J. A. Kairemo, and Antti P. Jekunen. "Somatostatin receptor imaging of olfactory neuroblastoma." Journal of Laryngology & Otology 110, no. 12 (December 1996): 1161–63. http://dx.doi.org/10.1017/s0022215100136023.
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AbstractNeural-crest tumours, including neuroblastomas, express somatostatin receptors. This can be shown by radionuclide labelling of octreotide, a somatostatin analogue. Studies on imaging with this substance have dealt with childhood neuroblastomas. Olfactory neuroblastoma (aesthesioneuroblastoma) is a rare tumour in which somatostatin receptor content has not been analysed, nor have radionuclide methods for diagnostic purposes been described. We report a case of olfactory neuroblastoma, in which scanning with m In-labelled octreotide was performed. A strong uptake was seen at the base of the skull. This was confirmed as a recurrent tumour by magnetic resonance (MR) imaging. Uptake was also observed in the neck and chest, indicating extensive spread of the disease.Somatostatin receptor expression has been shown to correlate with prognosis in childhood neuroblastoma. The accuracy of labelled octreotide in the diagnosis of olfactory neuroblastoma indicates that it might be useful in radionuclide therapy of patients with advanced disease, when no other treatment modalities are available.
11
De Wyn, Jolien, Mark W. Zimmerman, Nina Weichert-Leahey, Carolina Nunes, Belamy B. Cheung, Brian J. Abraham, Anneleen Beckers, et al. "MEIS2 Is an Adrenergic Core Regulatory Transcription Factor Involved in Early Initiation of TH-MYCN-Driven Neuroblastoma Formation." Cancers 13, no. 19 (September 24, 2021): 4783. http://dx.doi.org/10.3390/cancers13194783.
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Roughly half of all high-risk neuroblastoma patients present with MYCN amplification. The molecular consequences of MYCN overexpression in this aggressive pediatric tumor have been studied for decades, but thus far, our understanding of the early initiating steps of MYCN-driven tumor formation is still enigmatic. We performed a detailed transcriptome landscaping during murine TH-MYCN-driven neuroblastoma tumor formation at different time points. The neuroblastoma dependency factor MEIS2, together with ASCL1, was identified as a candidate tumor-initiating factor and shown to be a novel core regulatory circuit member in adrenergic neuroblastomas. Of further interest, we found a KEOPS complex member (gm6890), implicated in homologous double-strand break repair and telomere maintenance, to be strongly upregulated during tumor formation, as well as the checkpoint adaptor Claspin (CLSPN) and three chromosome 17q loci CBX2, GJC1 and LIMD2. Finally, cross-species master regulator analysis identified FOXM1, together with additional hubs controlling transcriptome profiles of MYCN-driven neuroblastoma. In conclusion, time-resolved transcriptome analysis of early hyperplastic lesions and full-blown MYCN-driven neuroblastomas yielded novel components implicated in both tumor initiation and maintenance, providing putative novel drug targets for MYCN-driven neuroblastoma.
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Larsson, Karin, Anna Kock, Helena Idborg, Marie Arsenian Henriksson, Tommy Martinsson, John I. Johnsen, Marina Korotkova, Per Kogner, and Per-Johan Jakobsson. "COX/mPGES-1/PGE2 pathway depicts an inflammatory-dependent high-risk neuroblastoma subset." Proceedings of the National Academy of Sciences 112, no. 26 (June 15, 2015): 8070–75. http://dx.doi.org/10.1073/pnas.1424355112.
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The majority of solid tumors are presented with an inflammatory microenvironment. Proinflammatory lipid mediators including prostaglandin E2 (PGE2) contribute to the establishment of inflammation and have been linked to tumor growth and aggressiveness. Here we show that high-risk neuroblastoma with deletion of chromosome 11q represents an inflammatory subset of neuroblastomas. Analysis of enzymes involved in the production of proinflammatory lipid mediators showed that 11q-deleted neuroblastoma tumors express high levels of microsomal prostaglandin E synthase-1 (mPGES-1) and elevated levels of PGE2. High mPGES-1 expression also corresponded to poor survival of neuroblastoma patients. Investigation of the tumor microenvironment showed high infiltration of tumor-promoting macrophages with high expression of the M2-polarization markers CD163 and CD206. mPGES-1–expressing cells in tumors from different subtypes of neuroblastoma showed differential expression of one or several cancer-associated fibroblast markers such as vimentin, fibroblast activation protein α, α smooth muscle actin, and PDGF receptor β. Importantly, inhibition of PGE2 production with diclofenac, a nonselective COX inhibitor, resulted in reduced tumor growth in an in vivo model of 11q-deleted neuroblastoma. Collectively, these results suggest that PGE2 is involved in the tumor microenvironment of specific neuroblastoma subgroups and indicate that therapeutic strategies using existing anti-inflammatory drugs in combination with current treatment should be considered for certain neuroblastomas.
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Kerbl, Reinhold, Christian E. Urban, Inge M. Ambros, Hans J. Dornbusch, Wolfgang Schwinger, Herwig Lackner, R. Ladenstein, V. Strenger, H. Gadner, and Peter F. Ambros. "Neuroblastoma Mass Screening in Late Infancy: Insights Into the Biology of Neuroblastic Tumors." Journal of Clinical Oncology 21, no. 22 (November 15, 2003): 4228–34. http://dx.doi.org/10.1200/jco.2003.10.168.
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Purpose: Neuroblastoma screening in early infancy has detected predominantly “favorable” tumors. We postponed screening to an age between 7 and 12 months to test whether this shift of screening age might influence the detection rate of genetically/clinically unfavorable tumors. Patients and Methods: In a 10-year period, 313,860 infants were screened by analysis of urine catecholamines. When a neuroblastoma was diagnosed, at least two different areas from every tumor were analyzed for genetic features (MYCN amplification, 1p status, ploidy). Furthermore, neuroblastoma incidence and mortality of the screened group and the cohort of 572,483 children not participating in the screening program were compared. Results: Forty-six neuroblastomas were detected by mass screening. In 17 tumors (37%) at least one of the biologic features was “unfavorable.” In 10 of 17 patients, one or more of these alterations were only focally present (tumor heterogeneity). In the screened cohort, neuroblastoma incidence was significantly higher when compared with unscreened children (18.2 v 11.2/100,000 births), while there was a trend towards lower incidence of stage 4 over 1 year (2.2 v 3.8). Mortality was not significantly different (0.96 v 1.57). Conclusion: In contrast to other neuroblastoma screening programs, more than one-third of patients were found with unfavorable genetic markers in our study. The high proportion of focal alterations suggests that biologically young neuroblastomas may consist of genetically favorable and unfavorable parts/areas/clones. We conclude that at least one-third of neuroblastomas detected by screening in late infancy are anticipated cases. This, however, does not result in significantly reduced mortality.
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Shim, Jenny, and Kelly C. Goldsmith. "A New Player in Neuroblastoma: YAP and Its Role in the Neuroblastoma Microenvironment." Cancers 13, no. 18 (September 16, 2021): 4650. http://dx.doi.org/10.3390/cancers13184650.
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Neuroblastoma is the most common extra-cranial pediatric solid tumor that accounts for more than 15% of childhood cancer-related deaths. High risk neuroblastomas that recur during or after intense multimodal therapy have a <5% chance at a second sustained remission or cure. The solid tumor microenvironment (TME) has been increasingly recognized to play a critical role in cancer progression and resistance to therapy, including in neuroblastoma. The Yes-Associated Protein (YAP) in the Hippo pathway can regulate cancer proliferation, tumor initiation, and therapy response in many cancer types and as such, its role in the TME has gained interest. In this review, we focus on YAP and its role in neuroblastoma and further describe its demonstrated and potential effects on the neuroblastoma TME. We also discuss the therapeutic strategies for inhibiting YAP in neuroblastoma.
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Hansson, Karin, Katarzyna Radke, Kristina Aaltonen, Jani Saarela, Adriana Mañas, Jonas Sjölund, Emma M. Smith, et al. "Therapeutic targeting of KSP in preclinical models of high-risk neuroblastoma." Science Translational Medicine 12, no. 562 (September 23, 2020): eaba4434. http://dx.doi.org/10.1126/scitranslmed.aba4434.
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Neuroblastoma is a childhood malignancy with often dismal prognosis; relapse is common despite intense treatment. Here, we used human tumor organoids representing multiple MYCN-amplified high-risk neuroblastomas to perform a high-throughput drug screen with approved or emerging oncology drugs. Tumor-selective effects were calculated using drug sensitivity scores. Several drugs with previously unreported anti-neuroblastoma effects were identified by stringent selection criteria. ARRY-520, an inhibitor of kinesin spindle protein (KSP), was among those causing reduced viability. High expression of the KSP-encoding gene KIF11 was associated with poor outcome in neuroblastoma. Genome-scale loss-of-function screens in hundreds of human cancer cell lines across 22 tumor types revealed that KIF11 is particularly important for neuroblastoma cell viability. KSP inhibition in neuroblastoma patient-derived xenograft (PDX) cells resulted in the formation of abnormal monoastral spindles, mitotic arrest, up-regulation of mitosis-associated genes, and apoptosis. In vivo, KSP inhibition caused regression of MYCN-amplified neuroblastoma PDX tumors. Furthermore, treatment of mice harboring orthotopic neuroblastoma PDX tumors resulted in increased survival. Our results suggested that KSP inhibition could be a promising treatment strategy in children with high-risk neuroblastoma.
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Lin, Ming-Chung, Yuan-Wen Lee, Yuan-Yun Tseng, Yung-Wei Lin, Jui-Tai Chen, Shing-Hwa Liu, and Ruei-Ming Chen. "Honokiol Induces Autophagic Apoptosis in Neuroblastoma Cells through a P53-Dependent Pathway." American Journal of Chinese Medicine 47, no. 04 (January 2019): 895–912. http://dx.doi.org/10.1142/s0192415x19500472.
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In children, neuroblastomas are the most common and deadly solid tumor. Our previous studies showed that honokiol can cross the blood–brain barrier and kill neuroblastoma cells. In this study, we further evaluated if exposure to honokiol for short periods could induce autophagy and subsequent apoptosis of neuroblastoma cells and possible mechanisms. Exposure of neuroblastoma neuro-2a cells to honokiol for 24[Formula: see text]h induced morphological shrinkage and cell death. As to the mechanisms, honokiol consecutively induced cytochrome c release from mitochondria, caspase-3 activation, DNA fragmentation and cell apoptosis. Separately, honokiol time-dependently augmented the proportion of autophagic cells and the ratio of light chain 3 (LC3)-II/LC3-I. Pretreatment of neuro-2a cells with 3-methyladenine, an inhibitor of autophagy, attenuated honokiol-induced cell autophagy, caspase-3 activation, DNA damage and cell apoptosis. In contrast, stimulation of autophagy by rapamycin, an inducer of autophagy, significantly enhanced honokiol-induced cell apoptosis. Furthermore, honokiol-induced autophagic apoptosis was confirmed in neuroblastoma NB41A3 cells. Knocking down translation of p53 using RNA interference attenuated honokiol-induced autophagy and apoptosis in neuro-2a and NB41A3 cells. Taken together, this study showed that at early periods, honokiol can induce autophagic apoptosis of neuroblastoma cells through activating a p53-dependent mechanism. Consequently, honokiol has the potential to be a therapeutic option for neuroblastomas.
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Wang, Wei, Xinjie Wang, Mehrdad Rajaei, Ji Youn Youn, Atif Zafar, Hemantkumar Deokar, John K. Buolamwini, et al. "Targeting MDM2 for Neuroblastoma Therapy: In Vitro and In Vivo Anticancer Activity and Mechanism of Action." Cancers 12, no. 12 (December 5, 2020): 3651. http://dx.doi.org/10.3390/cancers12123651.
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Background: Neuroblastoma is an aggressive pediatric solid tumor with an overall survival rate of <50% for patients with high-risk disease. The majority (>98%) of pathologically-diagnosed neuroblastomas have wild-type p53 with intact functional activity. However, the mouse double minute 2 (MDM2) homolog, an E3 ubiquitin ligase, is overexpressed in neuroblastoma and leads to inhibition of p53. MDM2 also exerts p53-independent oncogenic functions. Thus, MDM2 seems to be an attractive target for the reactivation of p53 and attenuation of oncogenic activity in neuroblastoma. Methods: In this study, we evaluated the anticancer activities and underlying mechanisms of action of SP141, a first-in-class MDM2 inhibitor, in neuroblastoma cell lines with different p53 backgrounds. The findings were confirmed in mouse xenograft models of neuroblastoma. Results: We demonstrate that SP141 reduces neuroblastoma cell viability, induces apoptosis, arrests cells at the G2/M phase, and prevents cell migration, independent of p53. In addition, in neuroblastoma xenograft models, SP141 inhibited MDM2 expression and suppressed tumor growth without any host toxicity at the effective dose. Conclusions: MDM2 inhibition by SP141 results in the inhibition of neuroblastoma growth and metastasis, regardless of the p53 status of the cells and tumors. These findings provide proof-of-concept that SP141 represents a novel treatment option for both p53 wild-type and p53 null neuroblastoma.
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Stepanova, Lilia, and Brian Sorrentino. "“Side Population” Cells in Mouse Neuroblastoma Express Abcg2 and Are Enriched for Neuroblastoma Stem Cells." Blood 108, no. 11 (November 16, 2006): 4268. http://dx.doi.org/10.1182/blood.v108.11.4268.4268.
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Abstract There is now accumulating evidence for the existence of rare cancer stem cells that resemble adult stem cells in their ability to replicate and produce more specialized cells constituting the bulk of the tumor. Neuroblastoma is the most common childhood cancer, developing extracranially from neuroblasts of the body. Approximately 70–80% of patients have metastatic disease at the time of diagnosis, and fewer than half of these patients are cured. Human neuroblastoma cells have been shown to contain a subpopulation of cells with a high capacity to efflux Hoechst 33342 nuclear dye, resulting in a distinct side population (SP) phenotype (Hirschmann-Jax et al., PNAS, 2004). These SP cells also express high levels of ABCG2 and ABCA3 transporter genes. We have used a mouse model to further investigate the relationship between the SP phenotype and Abcg2 expression in neuroblastoma stem cells. Mice, expressing N-myc in neural-crest cells, develop neuroblastomas at early age (Weiss et al., EMBO J, 1997). We have found that these neuroblastomas can be divided into three groups according to their SP phenotype; no SP cells present, low SP cells (0.6–2% of total cell number) and high SP cells (20–40% SP cells in total neuroblastoma cell population). When present, the SP fraction was significantly decreased after treatment of the cells with gleevec and fumitremorgin C, inhibitors of Abcg2 function ( 4.7% with treatment vs. 30.5% untreated in one case). This result indicates that Abcg2 is a major determinant of SP phenotype in these tumors. Quantitative PCR, performed on sorted SP and non-SP cells confirmed about 6 fold higher level of Abcg2 expression in the SP cell fraction in comparison with non-SP. In order to determine the clonogenic capacity of different tumor cell populations, varying numbers of tumor cells were injected in the flanks of NOD/SCID/gamma null mice. Transplantability of the tumors was found to correlate with SP phenotype. At a dose of 106 cells per recipient, neuroblastomas with no SP cells did not form tumors (0 tumors developed in 6 recipients). Neuroblastoma cells with low SP cell numbers (0.6% of total cells) formed tumors in 2 out of 4 transplants at this cell dose. Neuroblastomas with a high SP cell population (30% of the cells) had the highest clonogenic activity, forming tumors in 6 out of 6 transplants at 106 cells per injection. These results indicate that tumor stem cells are more abundant in high SP tumors in comparison with tumors with lower SP cell fractions. Next, sorting experiments based on the SP phenotype indicated that SP cells are enriched for neuroblastoma stem cells. In one experiment using a neuroblastoma sample with 22% SP cells, recipients were inoculated with a dose of 105 sorted cells. Three out of 4 mice formed tumors after transplantation with sorted SP cells while only 1 of 4 mice transplanted with non-SP cells developed tumors. Secondary tumors, developed from sorted SP cells, had themselves higher proportion of SP cells in comparison with tumors, developed from non-SP cells (35–40% and 8–10%, respectively). We are now using this genetic mouse model to further study the use of Abcg2 expression to isolate neuroblastoma stem cells.
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Macsek, Peter, Jan Skoda, Maria Krchniakova, Jakub Neradil, and Renata Veselska. "Iron-Chelation Treatment by Novel Thiosemicarbazone Targets Major Signaling Pathways in Neuroblastoma." International Journal of Molecular Sciences 23, no. 1 (December 29, 2021): 376. http://dx.doi.org/10.3390/ijms23010376.
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Despite constant advances in the field of pediatric oncology, the survival rate of high-risk neuroblastoma patients remains poor. The molecular and genetic features of neuroblastoma, such as MYCN amplification and stemness status, have established themselves not only as potent prognostic and predictive factors but also as intriguing targets for personalized therapy. Novel thiosemicarbazones target both total level and activity of a number of proteins involved in some of the most important signaling pathways in neuroblastoma. In this study, we found that di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) potently decreases N-MYC in MYCN-amplified and c-MYC in MYCN-nonamplified neuroblastoma cell lines. Furthermore, DpC succeeded in downregulating total EGFR and phosphorylation of its most prominent tyrosine residues through the involvement of NDRG1, a positive prognostic marker in neuroblastoma, which was markedly upregulated after thiosemicarbazone treatment. These findings could provide useful knowledge for the treatment of MYC-driven neuroblastomas that are unresponsive to conventional therapies.
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Martinez-Ciarpaglini, Carolina, Isidro Machado, Akihiko Yoshida, Gema Nieto, Ana P. Berbegall, Maria Teresa Blanquer-Maceíras, Rosa Noguera, Antonio Ferrández, and Samuel Navarro. "Extra-Adrenal Adult Neuroblastoma With Aberrant Germ Cell Marker Expression: Maturation After Chemotherapy as an Important Clue to a Challenging Diagnosis." International Journal of Surgical Pathology 27, no. 5 (March 24, 2019): 568–73. http://dx.doi.org/10.1177/1066896919835945.
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Adult neuroblastoma is an extremely infrequent neoplasm, usually occurring in the adrenal medulla or in the paraspinal sympathetic ganglia, as its childhood counterpart. We report a very unusual case of a Schwannian stroma-poor adult neuroblastoma of inguinal location, showing aberrant expression of germ cell markers: SALL4 and OCT4. This aberrant marker expression, the unusual positivity for NKX2.2 and the very scattered (instead of diffuse strong) PHOX2B expression, complicated the initial diagnosis. In this case, the posttreatment histological evaluation revealed the neuroblastic nature of the lesion. Neuroblastoma maturation after treatment is an unusual finding in adults, and in this case, added an important clue for the final diagnosis. Germs cells markers expression in neuroblastoma is an interesting feature to explore and may define a subset of neuroblastomas with a different biological nature.
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Pascual-Pasto, Guillem, Brendan McIntyre, Rawan Shraim, Samantha N. Buongervino, Amy K. Erbe, Doncho V. Zhelev, Shakhnozakhon Sadirova, et al. "GPC2 antibody–drug conjugate reprograms the neuroblastoma immune milieu to enhance macrophage-driven therapies." Journal for ImmunoTherapy of Cancer 10, no. 12 (December 2022): e004704. http://dx.doi.org/10.1136/jitc-2022-004704.
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BackgroundAntibody–drug conjugates (ADCs) that deliver cytotoxic drugs to tumor cells have emerged as an effective and safe anticancer therapy. ADCs may induce immunogenic cell death (ICD) to promote additional endogenous antitumor immune responses. Here, we characterized the immunomodulatory properties of D3-GPC2-PBD, a pyrrolobenzodiazepine (PBD) dimer-bearing ADC that targets glypican 2 (GPC2), a cell surface oncoprotein highly differentially expressed in neuroblastoma.MethodsADC-mediated induction of ICD was studied in GPC2-expressing murine neuroblastomas in vitro and in vivo. ADC reprogramming of the neuroblastoma tumor microenvironment was profiled by RNA sequencing, cytokine arrays, cytometry by time of flight and flow cytometry. ADC efficacy was tested in combination with macrophage-driven immunoregulators in neuroblastoma syngeneic allografts and human patient-derived xenografts.ResultsThe D3-GPC2-PBD ADC induced biomarkers of ICD, including neuroblastoma cell membrane translocation of calreticulin and heat shock proteins (HSP70/90) and release of high-mobility group box 1 and ATP. Vaccination of immunocompetent mice with ADC-treated murine neuroblastoma cells promoted T cell-mediated immune responses that protected animals against tumor rechallenge. ADC treatment also reprogrammed the tumor immune microenvironment to a proinflammatory state in these syngeneic neuroblastoma models, with increased tumor trafficking of activated macrophages and T cells. In turn, macrophage or T-cell inhibition impaired ADC efficacy in vivo, which was alternatively enhanced by both CD40 agonist and CD47 antagonist antibodies. In human neuroblastomas, the D3-GPC2-PBD ADC also induced ICD and promoted tumor phagocytosis by macrophages, which was further enhanced when blocking CD47 signaling in vitro and in vivo.ConclusionsWe elucidated the immunoregulatory properties of a GPC2-targeted ADC and showed robust efficacy of combination immunotherapies in diverse neuroblastoma preclinical models.
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Shmakova, Anna A., Polina S. Klimovich, Karina D. Rysenkova, Vladimir S. Popov, Anna S. Gorbunova, Anna A. Karpukhina, Maxim N. Karagyaur, Kseniya A. Rubina, Vsevolod A. Tkachuk, and Ekaterina V. Semina. "Urokinase Receptor uPAR Downregulation in Neuroblastoma Leads to Dormancy, Chemoresistance and Metastasis." Cancers 14, no. 4 (February 16, 2022): 994. http://dx.doi.org/10.3390/cancers14040994.
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uPAR is a membrane receptor that binds extracellular protease urokinase, contributes to matrix remodeling and plays a crucial role in cellular adhesion, proliferation, survival, and migration. uPAR overexpression in tumor cells promotes mitogenesis, opening a prospective avenue for targeted therapy. However, uPAR targeting in cancer has potential risks. We have recently shown that uPAR downregulation in neuroblastoma promotes epithelial-mesenchymal transition (EMT), potentially associated with metastasis and chemoresistance. We used data mining to evaluate the role of uPAR expression in primary and relapsed human neuroblastomas. To model the decreased uPAR expression, we targeted uPAR using CRISPR/Cas9 and shRNA in neuroblastoma Neuro2a cells and evaluated their chemosensitivity in vitro as well as tumor growth and metastasis in vivo. We demonstrate that the initially high PLAUR expression predicts poor survival in human neuroblastoma. However, relapsed neuroblastomas have a significantly decreased PLAUR expression. uPAR targeting in neuroblastoma Neuro2a cells leads to p38 activation and an increased p21 expression (suggesting a dormant phenotype). The dormancy in neuroblastoma cells can be triggered by the disruption of uPAR-integrin interaction. uPAR-deficient cells are less sensitive to cisplatin and doxorubicin treatment and exhibit lower p53 activation. Finally, low uPAR-expressing Neuro2a cells formed smaller primary tumors, but more frequent metastasis in mice. To the best of our knowledge, this is the first study revealing the pathological role of dormant uPAR-deficient cancer cells having a chemoresistant and motile phenotype.
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Gunda, Venugopal, Anup S. Pathania, Srinivas Chava, Philip Prathipati, Nagendra K. Chaturvedi, Don W. Coulter, Manoj K. Pandey, Donald L. Durden, and Kishore B. Challagundla. "Amino Acids Regulate Cisplatin Insensitivity in Neuroblastoma." Cancers 12, no. 9 (September 10, 2020): 2576. http://dx.doi.org/10.3390/cancers12092576.
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Neuroblastoma are pediatric, extracranial malignancies showing alarming survival prognosis outcomes due to their resilience to current aggressive treatment regimens, including chemotherapies with cisplatin (CDDP) provided in the first line of therapy regimens. Metabolic deregulation supports tumor cell survival in drug-treated conditions. However, metabolic pathways underlying cisplatin-resistance are least studied in neuroblastoma. Our metabolomics analysis revealed that cisplatin-insensitive cells alter their metabolism; especially, the metabolism of amino acids was upregulated in cisplatin-insensitive cells compared to the cisplatin-sensitive neuroblastoma cell line. A significant increase in amino acid levels in cisplatin-insensitive cells led us to hypothesize that the mechanisms upregulating intracellular amino acid pools facilitate insensitivity in neuroblastoma. We hereby report that amino acid depletion reduces cell survival and cisplatin-insensitivity in neuroblastoma cells. Since cells regulate their amino acids levels through processes, such as autophagy, we evaluated the effects of hydroxychloroquine (HCQ), a terminal autophagy inhibitor, on the survival and amino acid metabolism of cisplatin-insensitive neuroblastoma cells. Our results demonstrate that combining HCQ with CDDP abrogated the amino acid metabolism in cisplatin-insensitive cells and sensitized neuroblastoma cells to sub-lethal doses of cisplatin. Our results suggest that targeting of amino acid replenishing mechanisms could be considered as a potential approach in developing combination therapies for treating neuroblastomas.
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Guan, Jikui, Bengt Hallberg, and Ruth H. Palmer. "Chromosome Imbalances in Neuroblastoma—Recent Molecular Insight into Chromosome 1p-deletion, 2p-gain, and 11q-deletion Identifies New Friends and Foes for the Future." Cancers 13, no. 23 (November 24, 2021): 5897. http://dx.doi.org/10.3390/cancers13235897.
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Neuroblastoma is the most common extracranial solid pediatric tumor, with around 15% childhood cancer-related mortality. High-risk neuroblastomas exhibit a range of genetic, morphological, and clinical heterogeneities, which add complexity to diagnosis and treatment with existing modalities. Identification of novel therapies is a high priority in high-risk neuroblastoma, and the combination of genetic analysis with increased mechanistic understanding—including identification of key signaling and developmental events—provides optimism for the future. This focused review highlights several recent findings concerning chromosomes 1p, 2p, and 11q, which link genetic aberrations with aberrant molecular signaling output. These novel molecular insights contribute important knowledge towards more effective treatment strategies for neuroblastoma.
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Maris, John M., and Katherine K. Matthay. "Molecular Biology of Neuroblastoma." Journal of Clinical Oncology 17, no. 7 (July 1999): 2264. http://dx.doi.org/10.1200/jco.1999.17.7.2264.
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PURPOSE AND RESULTS: Neuroblastoma, the most common solid extracranial neoplasm in children, is remarkable for its clinical heterogeneity. Complex patterns of genetic abnormalities interact to determine the clinical phenotype. The molecular biology of neuroblastoma is characterized by somatically acquired genetic events that lead to gene overexpression (oncogenes), gene inactivation (tumor suppressor genes), or alterations in gene expression. Amplification of the MYCN proto-oncogene occurs in 20% to 25% of neuroblastomas and is a reliable marker of aggressive clinical behavior. No other oncogene has been shown to be consistently mutated or overexpressed in neuroblastoma, although unbalanced translocations resulting in gain of genetic material from chromosome bands 17q23-qter have been identified in more than 50% of primary tumors. Some children have an inherited predisposition to develop neuroblastoma, but a familial neuroblastoma susceptibility gene has not yet been localized. Consistent areas of chromosomal loss, including chromosome band 1p36 in 30% to 35% of primary tumors, 11q23 in 44%, and 14q23-qter in 22%, may identify the location of neuroblastoma suppressor genes. Alterations in the expression of the neurotrophins and their receptors correlate with clinical behavior and may reflect the degree of neuroblastic differentiation before malignant transformation. Alterations in the expression of genes that regulate apoptosis also correlate with neuroblastoma behavior and may help to explain the phenomenon of spontaneous regression observed in a well-defined subset of patients. CONCLUSION: The molecular biology of neuroblastoma has led to a combined clinical and biologic risk stratification. Future advances may lead to more specific treatment strategies for children with neuroblastoma.
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ROSTI, LUCA, ANGELA E. LIN, and ALESSANDRO FRIGIOLA. "Neuroblastoma and Congenital Cardiovascular Malformations." Pediatrics 97, no. 2 (February 1, 1996): 258–61. http://dx.doi.org/10.1542/peds.97.2.258.
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Congenital cardiovascular malformations (CCVM) are frequently associated with noncardiac malformations, often comprising a multiple malformation syndrome, but occurring infrequently in nonsyndromic systemic disease states such as neuroblastoma. As the most common malignancy in the first year of life, neuroblastoma presents as both clinically apparent and clinically unsuspected in situ tumors detected at autopsy. Neuroblastoma's association with CCVMs, especially conotruncal defects, suggests a possible common embryologic role for abnormal neural crest cell migration and development. We provide further documentation of this intriguing, albeit rare, association by reporting a boy with a prenatally detected complex CCVM (univentricular heart and dextro-transposition of the great arteries [d-TGA]) and congenital neuroblastoma.
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Dimić, Jovana, Dejan Skorić, Aleksandar Sretenović, and Slaviša Đuričić. "Primary hepatic neuroblastoma in a 19-month-old child: A case report." Medicinska istrazivanja 55, no. 2 (2022): 41–45. http://dx.doi.org/10.5937/medi55-28059.
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Introduction. Neuroblastoma in solid organs other than the sympathetic nervous system is extremely rare. The most common site of neuroblastoma is the adrenal medulla. Liver neuroblastomas are usually metastatic lesions, particularly from stage 4S adrenal neuroblastoma. Patient review. We report the first case of primary hepatic high-risk neuroblastoma diagnosed in a child older than 12 months. The patient received multimodal oncology treatment, including chemotherapy, surgery, bone marrow transplantation, radiotherapy, and immunotherapy, as well as deep regional hyperthermia. Despite the timely diagnosis, the tumor was refractory to intensive treatment, and the patient died 2.5 years after the diagnosis. Conclusion. The differential diagnosis of primary malignant liver tumors in pediatric patients should include neuro-blastoma, especially in tumors with atypical clinical presentation. The reports of similar cases in the future may contribute to better tumor biology understanding and facilitate clinical management.
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Woods, William C., Bernard Lemieux, and Mendel Tuchman. "Neuroblastoma Represents Distinct Clinical-Biologic Entities: A Review and Perspective From the Quebec Neuroblastoma Screening Project." Pediatrics 89, no. 1 (January 1, 1992): 114–18. http://dx.doi.org/10.1542/peds.89.1.114.
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Data are presented suggesting that neuroblastoma represents at least two distinct clinical-biologic entities. One, favorable neuroblastoma, is associated with young age and early stage at diagnosis, triploid karyotypes, no 1p abnormalities or N-myc gene amplification, more mature catecholamine synthesis and excretion, and excellent clinical outcome despite no or minimal therapy. The other, unfavorable neuroblastoma, is associated with older age and advanced stage, pseudodiploid karyotypes and 1p deletions, N-myc oncogene amplification, less mature catecholamine synthesis and excretion, and poor outcome despite aggressive multimodality therapy including bone marrow transplantation. Favorable neuroblastomas rarely, if ever, evolve into unfavorable disease. Unresolved issues regarding this hypothesis and implications for the efficacy of preclinical detection through mass screening are discussed.
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Roderwieser, Andrea, Frederik Sand, Esther Walter, Janina Fischer, Judith Gecht, Christoph Bartenhagen, Sandra Ackermann, et al. "Telomerase Is a Prognostic Marker of Poor Outcome and a Therapeutic Target in Neuroblastoma." JCO Precision Oncology, no. 3 (December 2019): 1–20. http://dx.doi.org/10.1200/po.19.00072.
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PURPOSE Telomere maintenance is a hallmark of high-risk neuroblastoma; however, the contribution of telomerase and alternative lengthening of telomeres (ALT) to clinical phenotypes has remained unclear. We aimed to determine the clinical relevance of telomerase activation versus ALT as biomarkers in pretreatment neuroblastoma and to assess the potential value of telomerase as a therapeutic target. MATERIALS AND METHODS The genomic status of TERT and MYCN was assessed in 457 pretreatment neuroblastomas by fluorescence in situ hybridization. ALT was examined in 273 of 457 tumors by detection of ALT-associated promyelocytic leukemia nuclear bodies, and TERT expression was determined by microarrays in 223 of these. Cytotoxic effects of telomerase-interacting compounds were analyzed in neuroblastoma cell lines in vitro and in vivo. RESULTS We detected TERT rearrangements in 46 of 457 cases (10.1%), MYCN amplification in 93 of 457 cases (20.4%), and elevated TERT expression in tumors lacking TERT or MYCN alterations in 10 of 223 cases (4.5%). ALT activation was found in 49 of 273 cases (17.9%). All these alterations occurred almost mutually exclusively and were associated with unfavorable prognostic variables and adverse outcome. The presence of activated telomerase (ie, TERT rearrangements, MYCN amplification, or high TERT expression without these alterations) was associated with poorest overall survival and was an independent prognostic marker in multivariable analyses. We also found that the telomerase-interacting compound 6-thio-2′-deoxyguanosine effectively inhibited viability and proliferation of neuroblastoma cells bearing activated telomerase. Similarly, tumor growth was strongly impaired upon 6-thio-2′-deoxyguanosine treatment in telomerase-positive neuroblastoma xenografts in mice. CONCLUSION Our data suggest telomerase activation and ALT define distinct neuroblastoma subgroups with adverse outcome and that telomerase may represent a promising therapeutic target in many high-risk neuroblastomas.
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Mazar, Joseph, Caleb Gordon, Varun Naga, and Tamarah J. Westmoreland. "The Killing of Human Neuroblastoma Cells by the Small Molecule JQ1 Occurs in a p53-Dependent Manner." Anti-Cancer Agents in Medicinal Chemistry 20, no. 13 (September 14, 2020): 1613–25. http://dx.doi.org/10.2174/1871520620666200424123834.
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Background: MYCN amplification is a prognostic biomarker associated with poor prognosis of neuroblastoma in children. The overall survival of children with MYCN-amplified neuroblastoma has only marginally improved within the last 20 years. The Bromodomain and Extra-Terminal motif (BET) inhibitor, JQ1, has been shown to downregulate MYCN in neuroblastoma cells. Objective: To determine if JQ1 downregulation of MYCN in neuroblastomas can offer a target- specific therapy for this, difficult to treat, pediatric cancer. Methods: Since MYCN-amplified neuroblastoma accounts for as much as 40 to 50 percent of all high-risk cases, we compared the effect of JQ1 on both MYCN-amplified and non-MYCN-amplified neuroblastoma cell lines and investigated its mechanism of action. Results: In this study, we show that JQ1 can specifically target MYCN for downregulation, though this effect is not specific to only MYCN-amplified cells. And although we can confirm that the loss of MYCN alone can induce apoptosis, the exogenous rescue of MYCN expression can abrogate much of this cytotoxicity. More fascinating, however, was the discovery that the JQ1-induced knockdown of MYCN, which led to the loss of the human double minute 2 homolog (HDM2) protein, also led to the accumulation of tumor protein 53 (also known as TP53 or p53), which ultimately induced apoptosis. Likewise, the knockdown of p53 also blunted the cytotoxic effects of JQ1. Conclusion: These data suggest a mechanism of action for JQ1 cytotoxicity in neuroblastomas and offer a possible prognostic target for determining its efficacy as a therapeutic.
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Scheer, Maximilian, Kaya Bork, Frieder Simon, Manimozhi Nagasundaram, Rüdiger Horstkorte, and Vinayaga Srinivasan Gnanapragassam. "Glycation Leads to Increased Polysialylation and Promotes the Metastatic Potential of Neuroblastoma Cells." Cells 9, no. 4 (April 2, 2020): 868. http://dx.doi.org/10.3390/cells9040868.
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Neuroblastoma is the second most frequent extracranial tumor, affecting young children worldwide. One hallmark of tumors such as neuroblastomas, is the expression of polysialic acid, which interferes with adhesion and may promote invasion and metastasis. Since tumor cells use glycolysis for energy production, they thereby produce as side product methylglyoxal (MGO), which reacts with proteins to advanced glycation end products in a mechanism called glycation. Here we analyzed the expression of (poly) sialic acid and adhesion of Kelly neuroblastoma cells after glycation with MGO. We found that both sialylation and polysialylation is increased after glycation. Furthermore, glycated Kelly neuroblastoma cells had a much higher potential for migration and invasion compared with non-glycated cells.
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Capone, Emily, Alessia Lamolinara, Fabio Pastorino, Roberta Gentile, Sara Ponziani, Giulia Di Vittorio, Daniela D’Agostino, et al. "Targeting Vesicular LGALS3BP by an Antibody-Drug Conjugate as Novel Therapeutic Strategy for Neuroblastoma." Cancers 12, no. 10 (October 15, 2020): 2989. http://dx.doi.org/10.3390/cancers12102989.
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Neuroblastoma is the most common extra-cranial solid tumor in infants and children, which accounts for approximately 15% of all cancer-related deaths in the pediatric population. New therapeutic modalities are urgently needed. Antibody-Drug Conjugates (ADC)s-based therapy has been proposed as potential strategy to treat this pediatric malignancy. LGALS3BP is a highly glycosylated protein involved in tumor growth and progression. Studies have shown that LGALS3BP is enriched in extracellular vesicles (EV)s derived by most neuroblastoma cells, where it plays a critical role in preparing a favorable tumor microenvironment (TME) through direct cross talk between cancer and stroma cells. Here, we describe the development of a non-internalizing LGALS3BP ADC, named 1959-sss/DM3, which selectively targets LGALS3BP expressing neuroblastoma. 1959-sss/DM3 mediated potent therapeutic activity in different types of neuroblastoma models. Notably, we found that treatments were well tolerated at efficacious doses that were fully curative. These results offer preclinical proof-of-concept for an ADC targeting exosomal LGALS3BP approach for neuroblastomas.
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Sawaisorn, Piamsiri, Korakot Atjanasuppat, Usanarat Anurathapan, Somchai Chutipongtanate, and Suradej Hongeng. "Strategies to Improve Chimeric Antigen Receptor Therapies for Neuroblastoma." Vaccines 8, no. 4 (December 11, 2020): 753. http://dx.doi.org/10.3390/vaccines8040753.
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Chimeric antigen receptors (CARs) are among the curative immunotherapeutic approaches that exploit the antigen specificity and cytotoxicity function of potent immune cells against cancers. Neuroblastomas, the most common extracranial pediatric solid tumors with diverse characteristics, could be a promising candidate for using CAR therapies. Several methods harness CAR-modified cells in neuroblastoma to increase therapeutic efficiency, although the assessment has been less successful. Regarding the improvement of CARs, various trials have been launched to overcome insufficient capacity. However, the reasons behind the inadequate response against neuroblastoma of CAR-modified cells are still not well understood. It is essential to update the present state of comprehension of CARs to improve the efficiency of CAR therapies. This review summarizes the crucial features of CARs and their design for neuroblastoma, discusses challenges that impact the outcomes of the immunotherapeutic competence, and focuses on devising strategies currently being investigated to improve the efficacy of CARs for neuroblastoma immunotherapy.
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Chandrasekaran, Sankkara Barathi, and Gopinath Vinayagamoorthy. "Predicting outcome of neuroblastoma using N-myc status and Trk-A expression." International Surgery Journal 6, no. 4 (March 26, 2019): 1226. http://dx.doi.org/10.18203/2349-2902.isj20191253.
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Background: Neuroblastoma is an embryonal cancer of the postganglionic sympathetic nervous system. It is the third most common pediatric cancer. The aim of the present study was to determine MYCN amplification and Trk-A expression in tissue samples of neuroblastoma cases and to correlate them with clinical status, stage and histopathology of the disease.Methods: This prospective study was conducted at the Institute of Child Health and hospital for children [ICH & HC], Egmore during the period from June 2011 to March 2012. Ten children of age between 8 months to 12 years diagnosed with neuroblastoma were included in the study. Tissue samples were collected from all patients and sent to evaluate histopathology to confirm the presence of neuroblastoma. Gene expression was studied using TaqMan quantitative RT-PCR. Immunohistochemistry of tissues samples were done to evaluate N-myc amplification and Trk A expression.Results: The most common presenting symptom was mass in the abdomen (60%) in the patients. In majority, stage 3 neuroblastoma was noticed in 5 (50%) cases. On histopathology, 2 (20%) cases were identified of ganglioneuro-blastoma, and 8 (80%) cases as neuroblastoma. N-myc was amplified in 3 cases (30%). No amplification was noted in all 3 cases (0%) of stage 1. None of the case in this study group showed Trk-A expression.Conclusions: N-myc amplification was well correlated with the stages of neuroblastoma. It should be considered to be as an important prognostic marker to select appropriate treatment in children with neuroblastomas.
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Sharkey, Brandon, Kaitlin Michelle Conner, Cade R. McGarvey, Ajay Nair, Abbigail Dorn, Kevin Reinard, and Brandon Gabel. "Pediatric central nervous system (CNS) neuroblastoma: A case report." Surgical Neurology International 15 (May 17, 2024): 162. http://dx.doi.org/10.25259/sni_794_2023.
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Background: Neuroblastomas are rare tumors activated by the FoxR2 gene commonly found in pediatric patients. Due to the novelty of these tumors, there is no standard diagnostic profile. However, they have been found to express Olig2, MAP2, SOX10, ANKRD55, and synaptophysin, and they can be identified with magnetic resonance imaging (MRI). Treatment with chemotherapy combined with stem cell rescue and craniospinal irradiation can improve non-infant patient outcomes. Case Description: We report a case of a 2-year-old patient who was diagnosed with a neuroblastoma through MRI imaging and pathology that confirmed FoxR2 gene activation. The tumor was successfully removed. However, the tumor was not high-grade like most FoxR2 neuroblastomas. Conclusion: The unusual presentation of a low-grade FoxR2 neuroblastoma demonstrates the necessity to conduct further research into the characteristics of these tumors.
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Szemes, Marianna, Zsombor Melegh, Jacob Bellamy, Alexander Greenhough, Madhu Kollareddy, Daniel Catchpoole, and Karim Malik. "A Wnt-BMP4 Signaling Axis Induces MSX and NOTCH Proteins and Promotes Growth Suppression and Differentiation in Neuroblastoma." Cells 9, no. 3 (March 23, 2020): 783. http://dx.doi.org/10.3390/cells9030783.
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The Wnt and bone morphogenetic protein (BMP) signaling pathways are known to be crucial in the development of neural crest lineages, including the sympathetic nervous system. Surprisingly, their role in paediatric neuroblastoma, the prototypic tumor arising from this lineage, remains relatively uncharacterised. We previously demonstrated that Wnt/β-catenin signaling can have cell-type-specific effects on neuroblastoma phenotypes, including growth inhibition and differentiation, and that BMP4 mRNA and protein were induced by Wnt3a/Rspo2. In this study, we characterised the phenotypic effects of BMP4 on neuroblastoma cells, demonstrating convergent induction of MSX homeobox transcription factors by Wnt and BMP4 signaling and BMP4-induced growth suppression and differentiation. An immunohistochemical analysis of BMP4 expression in primary neuroblastomas confirms a striking absence of BMP4 in poorly differentiated tumors, in contrast to a high expression in ganglion cells. These results are consistent with a tumor suppressive role for BMP4 in neuroblastoma. RNA sequencing following BMP4 treatment revealed induction of Notch signaling, verified by increases of Notch3 and Hes1 proteins. Together, our data demonstrate, for the first time, Wnt-BMP-Notch signaling crosstalk associated with growth suppression of neuroblastoma.
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Decaesteker, Bieke, Kaat Durinck, Nadine Van Roy, Bram De Wilde, Christophe Van Neste, Stéphane Van Haver, Stephen Roberts, Katleen De Preter, Vanessa Vermeirssen, and Frank Speleman. "From DNA Copy Number Gains and Tumor Dependencies to Novel Therapeutic Targets for High-Risk Neuroblastoma." Journal of Personalized Medicine 11, no. 12 (December 3, 2021): 1286. http://dx.doi.org/10.3390/jpm11121286.
Full textAbstract:
Neuroblastoma is a pediatric tumor arising from the sympatho-adrenal lineage and a worldwide leading cause of childhood cancer-related deaths. About half of high-risk patients die from the disease while survivors suffer from multiple therapy-related side-effects. While neuroblastomas present with a low mutational burden, focal and large segmental DNA copy number aberrations are highly recurrent and associated with poor survival. It can be assumed that the affected chromosomal regions contain critical genes implicated in neuroblastoma biology and behavior. More specifically, evidence has emerged that several of these genes are implicated in tumor dependencies thus potentially providing novel therapeutic entry points. In this review, we briefly review the current status of recurrent DNA copy number aberrations in neuroblastoma and provide an overview of the genes affected by these genomic variants for which a direct role in neuroblastoma has been established. Several of these genes are implicated in networks that positively regulate MYCN expression or stability as well as cell cycle control and apoptosis. Finally, we summarize alternative approaches to identify and prioritize candidate copy-number driven dependency genes for neuroblastoma offering novel therapeutic opportunities.
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Liu, Zhichao, and Changchun Li. "Identification of the Novel Methylated Genes’ Signature to Predict Prognosis in INRG High-Risk Neuroblastomas." Journal of Oncology 2021 (September 13, 2021): 1–10. http://dx.doi.org/10.1155/2021/1615201.
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Background. Neuroblastomas are the most frequent extracranial pediatric solid tumors. The prognosis of children with high-risk neuroblastomas has remained poor in the past decade. A powerful signature is required to identify factors associated with prognosis and improved treatment selection. Here, we identified a strong methylation signature that favored the earlier diagnosis of neuroblastoma in patients. Methods. Gene methylation (GM) data of neuroblastoma patients from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) were analyzed using a multivariate Cox regression analysis (MCRA) and univariate Cox proportional hazards regression analysis (UCPHRA). Results. The methylated genes’ signature consisting of eight genes (NBEA, DDX28, TMED8, LOC151174, EFNB2, GHRHR, MIMT1, and SLC29A3) was selected. The signature divided patients into low- and high-risk categories, with statistically significant survival rates (median survival time: 25.08 vs. >128.80 months, log-rank test, P < 0.001 ) in the training group, and the validation of the signature’s risk stratification ability was carried out in the test group (log-rank test, P < 0.01 , median survival time: 30.48 vs. >120.36 months). The methylated genes’ signature was found to be an independent predictive factor for neuroblastoma by MCRA. Functional enrichment analysis suggested that these methylated genes were related to butanoate metabolism, beta-alanine metabolism, and glutamate metabolism, all playing different significant roles in the process of energy metabolism in neuroblastomas. Conclusions. The set of eight methylated genes could be used as a new predictive and prognostic signature for patients with INRG high-risk neuroblastomas, thus assisting in treatment, drug development, and predicting survival.
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D'ACUNTO, C., H. GBELCOVÁ, R. KAPLÁNEK, M. POSPÍŠILOVÁ, M. HAVLÍK, and T. RUML. "Chelators as Antineuroblastomas Agents." Physiological Research 72, S3 (October 23, 2023): S277—S286. http://dx.doi.org/10.33549/physiolres.935184.
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Neuroblastoma represents 8-10 % of all malignant tumors in childhood and is responsible for 15 % of cancer deaths in the pediatric population. Aggressive neuroblastomas are often resistant to chemotherapy. Canonically, neuroblastomas can be classified according to the MYCN (N-myc proto-oncogene protein) gene amplification, a common marker of tumor aggressiveness and poor prognosis. It has been found that certain compounds with chelating properties may show anticancer activity, but there is little evidence for the effect of chelators on neuroblastoma. The effect of new chelators characterized by the same functional group, designated as HLZ (1-hydrazino phthalazine), on proliferation (WST-1 and methylene blue assay), cell cycle (flow cytometry), apoptosis (proliferation assay after use of specific pharmacological inhibitors and western blot analysis) and ROS production (fluorometric assay based on dichlorofluorescein diacetate metabolism) was studied in three neuroblastoma cell lines with different levels of MYCN amplification. The molecules were effective only on MYCN-non-amplified cells in which they arrested the cell cycle in the G0/G1 phase. We investigated the mechanism of action and identified the activation of cell signaling that involves protein kinase C.
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Szymansky, Annabell, Louisa-Marie Kruetzfeldt, Lukas C. Heukamp, Falk Hertwig, Jessica Theissen, Hedwig E. Deubzer, Eva-Maria Willing, et al. "Neuroblastoma Risk Assessment and Treatment Stratification with Hybrid Capture-Based Panel Sequencing." Journal of Personalized Medicine 11, no. 8 (July 22, 2021): 691. http://dx.doi.org/10.3390/jpm11080691.
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For many years, the risk-based therapy stratification of children with neuroblastoma has relied on clinical and molecular covariates. In recent years, genome analysis has revealed further alterations defining risk, tumor biology, and therapeutic targets. The implementation of a robust and scalable method for analyzing traditional and new molecular markers in routine diagnostics is an urgent clinical need. Here, we investigated targeted panel sequencing as a diagnostic approach to analyze all relevant genomic neuroblastoma risk markers in one assay. Our “neuroblastoma hybrid capture sequencing panel” (NB-HCSP) assay employs a technology for the high-coverage sequencing (>1000×) of 55 selected genes and neuroblastoma-relevant genomic regions, which allows for the detection of single nucleotide changes, structural rearrangements, and copy number alterations. We validated our assay by analyzing 15 neuroblastoma cell lines and a cohort of 20 neuroblastomas, for which reference routine diagnostic data and genome sequencing data were available. We observed a high concordance for risk markers identified by the NB-HSCP assay, clinical routine diagnostics, and genome sequencing. Subsequently, we demonstrated clinical applicability of the NB-HCSP assay by analyzing routine clinical samples. We conclude that the NB-HCSP assay may be implemented into routine diagnostics as a single assay that covers all essential covariates for initial neuroblastoma classification, extended risk stratification, and targeted therapy selection.
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Wu, Zhiyang, Patrick Hundsdoerfer, Johannes H. Schulte, Kathy Astrahantseff, Senguel Boral, Karin Schmelz, Angelika Eggert, and Oliver Klein. "Discovery of Spatial Peptide Signatures for Neuroblastoma Risk Assessment by MALDI Mass Spectrometry Imaging." Cancers 13, no. 13 (June 25, 2021): 3184. http://dx.doi.org/10.3390/cancers13133184.
Full textAbstract:
Risk classification plays a crucial role in clinical management and therapy decisions in children with neuroblastoma. Risk assessment is currently based on patient criteria and molecular factors in single tumor biopsies at diagnosis. Growing evidence of extensive neuroblastoma intratumor heterogeneity drives the need for novel diagnostics to assess molecular profiles more comprehensively in spatial resolution to better predict risk for tumor progression and therapy resistance. We present a pilot study investigating the feasibility and potential of matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to identify spatial peptide heterogeneity in neuroblastoma tissues of divergent current risk classification: high versus low/intermediate risk. Univariate (receiver operating characteristic analysis) and multivariate (segmentation, principal component analysis) statistical strategies identified spatially discriminative risk-associated MALDI-based peptide signatures. The AHNAK nucleoprotein and collapsin response mediator protein 1 (CRMP1) were identified as proteins associated with these peptide signatures, and their differential expression in the neuroblastomas of divergent risk was immunohistochemically validated. This proof-of-concept study demonstrates that MALDI-MSI combined with univariate and multivariate analysis strategies can identify spatially discriminative risk-associated peptide signatures in neuroblastoma tissues. These results suggest a promising new analytical strategy improving risk classification and providing new biological insights into neuroblastoma intratumor heterogeneity.
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Jiménez, Carlos, Roberta Antonelli, Marc Masanas, Aroa Soriano, Laura Devis-Jauregui, Jessica Camacho, Ainara Magdaleno, et al. "Neuronal Differentiation-Related Epigenetic Regulator ZRF1 Has Independent Prognostic Value in Neuroblastoma but Is Functionally Dispensable In Vitro." Cancers 13, no. 19 (September 28, 2021): 4845. http://dx.doi.org/10.3390/cancers13194845.
Full textAbstract:
Neuroblastoma is a pediatric tumor of the peripheral nervous system that accounts for up to ~15% of all cancer-related deaths in children. Recently, it has become evident that epigenetic deregulation is a relevant event in pediatric tumors such as high-risk neuroblastomas, and a determinant for processes, such as cell differentiation blockade and sustained proliferation, which promote tumor progression and resistance to current therapies. Thus, a better understanding of epigenetic factors implicated in the aggressive behavior of neuroblastoma cells is crucial for the development of better treatments. In this study, we characterized the role of ZRF1, an epigenetic activator recruited to genes involved in the maintenance of the identity of neural progenitors. We combined analysis of patient sample expression datasets with loss- and gain-of-function studies on neuroblastoma cell lines. Functional analyses revealed that ZRF1 is functionally dispensable for those cellular functions related to cell differentiation, proliferation, migration, and invasion, and does not affect the cellular response to chemotherapeutic agents. However, we found that high levels of ZRF1 mRNA expression are associated to shorter overall survival of neuroblastoma patients, even when those patients with the most common molecular alterations used as prognostic factors are removed from the analyses, thereby suggesting that ZRF1 expression could be used as an independent prognostic factor in neuroblastoma.
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Bergaggio, Elisa, Wei-Tien Tai, Andrea Aroldi, Carmen Mecca, Elisa Landoni, Manuel Nüesch, Ines Mota, et al. "Abstract 50: ALK inhibitors increase ALK expression and sensitize neuroblastoma cells to ALK.CAR-T cells." Cancer Research 84, no. 6_Supplement (March 22, 2024): 50. http://dx.doi.org/10.1158/1538-7445.am2024-50.
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Abstract Neuroblastoma is the most common extracranial solid tumor of childhood, with limited success in treating refractory or relapsed cases using current therapies. Chimeric antigen receptor (CAR) T cell therapy targeting GD2 has shown promise in neuroblastoma treatment, but relapses are associated with loss of antigen expression. The selection of the best tumor antigen is critical for the therapeutic success of CAR-T cells in hematologic malignancies and solid tumors. The Anaplastic Lymphoma Kinase (ALK) receptor is expressed by most neuroblastomas while virtually absent in most normal tissues. ALK is an oncogenic driver in neuroblastoma and ALK inhibitors show promising clinical activity. All these features make ALK an attractive target for CAR-T cell therapy. We developed ALK.CAR-T cells that show potent efficacy in monotherapy against neuroblastoma with high ALK expression without toxicity. For neuroblastoma with low ALK expression, combination with ALK inhibitors specifically potentiates ALK.CAR-T cells but not GD2.CAR-T cells. In neuroblastoma cell lines and in a patient-derived xenograft (PDX), the combination of ALK inhibitors and ALK.CAR-T cells significantly reduced tumor growth and extended mice survival. Mechanistically, ALK inhibitors impair tumor growth and upregulate the expression of ALK, thereby facilitating the activity of ALK.CAR-T cells against neuroblastoma. Thus, while neither ALK inhibitors nor ALK.CAR-T cells will likely be sufficient as monotherapy in neuroblastoma with low ALK density, their combination specifically enhances therapeutic efficacy. These findings provide insights into the potential of ALK.CAR-T cells as a novel therapeutic strategy for neuroblastoma. A Phase I clinical trial to test ALK.CAR-T cells in combination with ALK TKIs in children with refractory/relapsed neuroblastoma is being implemented based on these results. Citation Format: Elisa Bergaggio, Wei-Tien Tai, Andrea Aroldi, Carmen Mecca, Elisa Landoni, Manuel Nüesch, Ines Mota, Jasna Metovic, Luca Molinaro, Leyuan Ma, Diego Alvarado, Chiara Ambrogio, Claudia Voena, Rafael B. Blasco, Tongqing Li, Daryl Klein, Darrell J. Irvine, Mauro Papotti, Barbara Savolodo, Gianpietro Dotti, Roberto Chiarle. ALK inhibitors increase ALK expression and sensitize neuroblastoma cells to ALK.CAR-T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 50.
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Yang, Yaoli Pu, Simeng Wang, Xingguo Li, and Nina F. Schor. "Cell Line-Dependent Variability of Coordinate Expression of p75NTR and CRABP1 and Modulation of Effects of Fenretinide on Neuroblastoma Cells." Oxidative Medicine and Cellular Longevity 2016 (2016): 1–8. http://dx.doi.org/10.1155/2016/7568287.
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Neuroblastoma is a childhood neural crest tumor. Fenretinide, a retinoic acid analogue, induces accumulation of mitochondrial reactive oxygen species and consequent apoptosis in neuroblastoma cells. The p75 neurotrophin receptor (p75NTR) enhances the antineuroblastoma cell efficacy of fenretinidein vitro. We examined the role of the retinoid binding protein, CRABP1, in p75NTR-mediated potentiation of the efficacy of fenretinide. Knockdown and overexpression, respectively, of either p75NTR or CRABP1 were effected in neuroblastoma cell lines using standard techniques. Expression was determined by qRT-PCR and confirmed at the protein level by Western blot. Metabolic viability was determined by Alamar blue assay. While protein content of CRABP1 correlated roughly with that of p75NTR in the three neuroblastoid or epithelioid human neuroblastoma cell lines studied, manipulation of p75NTR expression resulted in cell line-dependent, variable change in CRABP1 expression. Furthermore, in some cell lines, induced expression of CRABP1 in the absence of p75NTR did not alter cell sensitivity to fenretinide treatment. The effects of manipulation of p75NTR expression on CRABP1 expression and the effects of CRABP1 expression on fenretinide efficacy are therefore neuroblastoma cell line-dependent. Potentiation of the antineuroblastoma cell effects of fenretinide by p75NTR is not mediated solely through CRABP1.
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Oldridge, Derek A., Bao Truong, Douglas Russ, Steven G. DuBois, Zalman Vaksman, Yael P. Mosse, Sharon J. Diskin, John M. Maris, and Katherine K. Matthay. "Differences in Genomic Profiles and Outcomes Between Thoracic and Adrenal Neuroblastoma." JNCI: Journal of the National Cancer Institute 111, no. 11 (February 21, 2019): 1192–201. http://dx.doi.org/10.1093/jnci/djz027.
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Abstract Background Neuroblastoma is a biologically and clinically heterogeneous disease. Based on recent studies demonstrating an association between the primary tumor site, prognosis, and commonly measured tumor biological features, we hypothesized that neuroblastomas arising in different sites would show distinct genomic features reflective of the developmental biology of the sympathicoadrenal nervous system. Methods We first compared genomic and epigenomic data of primary diagnostic neuroblastomas originating in the adrenal gland (n = 646) compared to thoracic sympathetic ganglia (n = 118). We also evaluated association of common germline variation with these primary sites in 1027 European-American neuroblastoma patients. Results We observed higher rates of MYCN amplification, chromosome 1q gain, and chromosome 11q deletion among adrenal tumors, which were highly predictive of functional RNA signatures. Surprisingly, thoracic neuroblastomas were more likely to harbor ALK driver mutations than adrenal cases among all cases (odds ratio = 1.89, 95% confidence interval = 1.04 to 3.43), and among cases without MYCN amplification (odds ratio = 2.86, 95% confidence interval = 1.48 to 5.49). Common germline single nucleotide polymorphisms (SNPs) in BARD1 (previously associated with high-risk neuroblastoma) were found to be strongly associated with predisposition for origin at adrenal, rather than thoracic, sites. Conclusions Neuroblastomas arising in the adrenal gland are more likely to harbor structural DNA aberrations including MYCN amplification, whereas thoracic tumors show defects in mitotic checkpoints resulting in hyperdiploidy. Despite the general association of ALK mutations with high-risk disease, thoracic tumors are more likely to harbor gain-of-function ALK aberrations. Site of origin is likely reflective of stage of sympathetic nervous system development when malignant transformation occurs and is a surrogate for underlying tumor biology.
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Ackermann, Sandra, Maria Cartolano, Barbara Hero, Anne Welte, Yvonne Kahlert, Andrea Roderwieser, Christoph Bartenhagen, et al. "A mechanistic classification of clinical phenotypes in neuroblastoma." Science 362, no. 6419 (December 6, 2018): 1165–70. http://dx.doi.org/10.1126/science.aat6768.
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Neuroblastoma is a pediatric tumor of the sympathetic nervous system. Its clinical course ranges from spontaneous tumor regression to fatal progression. To investigate the molecular features of the divergent tumor subtypes, we performed genome sequencing on 416 pretreatment neuroblastomas and assessed telomere maintenance mechanisms in 208 of these tumors. We found that patients whose tumors lacked telomere maintenance mechanisms had an excellent prognosis, whereas the prognosis of patients whose tumors harbored telomere maintenance mechanisms was substantially worse. Survival rates were lowest for neuroblastoma patients whose tumors harbored telomere maintenance mechanisms in combination with RAS and/or p53 pathway mutations. Spontaneous tumor regression occurred both in the presence and absence of these mutations in patients with telomere maintenance–negative tumors. On the basis of these data, we propose a mechanistic classification of neuroblastoma that may benefit the clinical management of patients.
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Fang, Xiaolian, Huanmin Wang, Xiaoli Ma, Yongli Guo, Wei Yang, Shoulong Hu, Yue Qiu, Junyang Zhao, and Xin Ni. "Clinical Features of Children with Retinoblastoma and Neuroblastoma." Journal of Ophthalmology 2020 (July 10, 2020): 1–8. http://dx.doi.org/10.1155/2020/9315784.
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Purpose. Retinoblastoma and neuroblastoma are the most common malignant extracranial solid tumors in children. This study aimed to summarize the clinical features, especially the delayed diagnosis in children with retinoblastoma and neuroblastoma. Methods. In a single hospital-based case-control study, a retrospective cohort of 175 children with retinoblastoma and neuroblastoma diagnosed from January 2016 to January 2018 were reviewed. The state of enucleation in retinoblastomas and pathological prognosis in neuroblastomas were outcome indicators. Hereby, the patients were divided into two groups, and clinical features including age at presentation and delayed diagnosis were compared. Results. A total of 112 patients with retinoblastoma and 63 with neuroblastoma were included. In the retinoblastoma cohort, the median age at presentation was 17.2 months (0.3–110 months). The mean delay of diagnosis was 1.6 ± 2.3 months, and the rate of enucleation was 61.6%. Unilateral disease, the International Classification of Intraocular Retinoblastoma (IIRC) stage E, and delay of diagnosis over 2.5 months were independent risk factors of ocular outcomes. Notably, the risk of enucleation was increased by 474% when the delay was longer than 2.5 months. In the neuroblastoma cohort, the delay of diagnosis of the unfavorable histology (UH) group was longer than that of the favorable histology (FH) group (1.9 months vs. 1.4 months, P=.487). The levels of serum ferritin and neuron-specific enolase were higher in the UH group than in the FH group (P<.05). Conclusions. This study summarized the clinical features and diagnosis biomarkers of retinoblastoma and neuroblastoma patients in China. These results might help to focus on early detection and treatment in children with retinoblastoma and neuroblastoma.
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Yan, Benedict, Malcolm Lim, Lihan Zhou, Chik Hong Kuick, May Ying Leong, Kol Jia Yong, LeLe Aung, Manuel Salto-Tellez, and Kenneth T. E. Chang. "Identification of MET genomic amplification, protein expression and alternative splice isoforms in neuroblastomas." Journal of Clinical Pathology 66, no. 11 (June 25, 2013): 985–91. http://dx.doi.org/10.1136/jclinpath-2012-201375.
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BackgroundCrizotinib, a dual anaplastic lymphoma kinase (ALK) and mesenchymal-epithelial transition (MET) tyrosine kinase inhibitor, is currently being evaluated for the treatment of neuroblastoma. Its effects are thought to be mediated mainly via its activity against ALK. Although MET genomic/protein expression status might conceivably affect crizotinib efficacy, this issue has hitherto not received attention in neuroblastomas.Aims/MethodsMET genomic and protein expression status was characterised by silver in situ hybridisation and immunohistochemistry (IHC) respectively, in a cohort of 54 neuroblastoma samples. MET splice isoforms were characterised in 15 of these samples by quantitative PCR.ResultsOne case (1/54; prevalence 1.85%) displayed MET genomic amplification, while another case (1/54; prevalence 1.85%) displayed strong membranous MET protein expression (IHC score 3+). Alternative exon 10-deleted and exon 14-deleted MET splice isoforms were identified.ConclusionsMET amplification and protein expression, although low in prevalence, are present in neuroblastomas. This has implications when crizotinib is employed as a therapeutic agent in neuroblastomas. Additionally, the existence of alternatively spliced MET isoforms may have clinical and biological implications in neuroblastomas.
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McNerney, Kevin Owen, Hamid Bassiri, Spyridon Karageorgos, and Priya Khurana. "3502 Stimulating iNKT Cell-Mediated Neuroblastoma Cytotoxicity in a Mouse Model." Journal of Clinical and Translational Science 3, s1 (March 2019): 21. http://dx.doi.org/10.1017/cts.2019.53.
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OBJECTIVES/SPECIFIC AIMS: Overall Research Aim: To develop an iNKT-cell engaging reagent (“CAb”)to induce neuroblastoma-directed cytotoxicity in vitro and in a mouse model of neuroblastoma. Objective 1: Explore the contribution of different GD2 affinities to the cytotoxicity against neuroblastoma cells in vitro. Objective 2: Deteremine whether use of different stimulatory glycolipids (alpha-GalCer vs. C34) alter the activation and cytotoxicity of iNKT cells against neuroblastoma in vitro. Objective 3: To analyze survival of an immunocompetent mouse model of neuroblastoma treated with C34-loaded vs alpha-GalCer-loaded CAb molecule, and to analyze the tumor microenvironment in each treatment condition. METHODS/STUDY POPULATION: CAb molecule will be generated by fusing a CD1d protein to an scFv domain for GD2 using cloning techniques. Previous work by our group has used a streptavidin-biotin system to link CD1d to an antibody against GD2, which is large and immunogenic. Protein expression of this novel fusion protein will occur in HEK293 cells. This new CAb molecule will then be loaded with alpha-GalCer or C34 for use in cytotoxicity and in vivo experiments. Cytotoxicity Assessment: Chromium assays will be used to assess the specific cytotoxicity generated by iNKT cells against neuroblastoma cells in vitro. iNKT cells will be activated by “CAb’s” with relatively high and low affinity for GD2, and also with Alpha-GalCer and C34 glycolipid antigen. flow cytometry will be used to assess for CD107a and Interferon Gamma. Mouse Model of Neuroblastoma: TH-MYCN +/+ mice will be used as an immunocompetent model of neuroblastoma. These mice have the MYCN gene under the control of a tyrosine hydroxylase promoter, and spontaneously develop neuroblastomas by 2 weeks of life which are uniformly fatal by 8 weeks of life. In vivo survival studies will be conducted by injecting CAb of relatively high and low affinity, loaded with glycolipid antigen intraperitonealy into TH-MYCN+/+ mice starting at 2 weeks of age, twice weekly. There will also be a matched negative control. Treatment groups are listed below: 1. alpha-GalCer loaded high-affinity Cab 2. alpha-GalCer loaded low-affinity Cab 3. C34-loaded high-affinity Cab 4. C34-loaded low-affinity Cab 5. Unloaded high-affinity Cab 6. Unloaded low-affinity Cab Enrollment will be 6 mice per group for the survival curves. Tumor Microenvironment analysis: 2 additional mice will be included in each group listed above to be sacrificed 2 weeks into treatment for tumor assessment with flow cytomtetry for iNKT cell, NK cell, T-Lymphocyte frequencies as well as interferon-Gamma expression. RESULTS/ANTICIPATED RESULTS: Objective 1: We expect to find that the highest affinity scFv domains for GD2 result in the greatest amount of cytotoxicity against neuroblastoma cells via iNKT cells. Objective 2: We expect that the C34 molecule will induce the greatest amounts of iNKT cell activation against neuroblastoma cells and higher cytotoxicity against neuroblastoma, which has not been shown previously. Objective 3: We expect to see prolonged survival of mice treated with the high affinity GD2 CAb loaded with C34 or alpha GalCer compared with the low affinity CAb loaded with C34 or alpha GalCer. We also expect that the C34 loaded CAb in both groups will have prolonged survival when compared with the alpha-GalCer loaded CAbs of either affinity. DISCUSSION/SIGNIFICANCE OF IMPACT: iNKT cells have been shown previously to confer an improved prognosis in neuroblastoma and other malignancies. Furthermore, high risk neuroblastomas tend to downregulate expression of a chemokine that attracts iNKT’s to the site of the neuroblastoma. Directing iNKT to the site of neuroblastoma holds promise as an effective immunotherapy option. Our preliminary data demonstrate that CAbs directed against GD2 are capable of exerting cytotoxicity of neuroblastoma in vitro. Furthermore a trend towards prolonged survival has been shown in TH-MYCN mice in early experiments. The development of a novel antibody that has reduced immunogenicity, incorporates a glycolipid antigen that does not induce iNKT cell anergy, and is specific for the GD2 tumor specific antigen has potential to result in increased iNKT-mediate neuroblastoma cytotoxicity and prolonged survival in TH-MYCN+/+ mice.
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Martínez-Sanz, Paula, Arjan J. Hoogendijk, Paul J. J. H. Verkuijlen, Karin Schornagel, Robin van Bruggen, Timo K. van den Berg, Godelieve A. M. Tytgat, Katka Franke, Taco W. Kuijpers, and Hanke L. Matlung. "CD47-SIRPα Checkpoint Inhibition Enhances Neutrophil-Mediated Killing of Dinutuximab-Opsonized Neuroblastoma Cells." Cancers 13, no. 17 (August 24, 2021): 4261. http://dx.doi.org/10.3390/cancers13174261.
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High-risk neuroblastoma, especially after recurrence, still has a very low survival rate. Immune checkpoint inhibitors targeting T cells have shown remarkable clinical efficacy in adult solid tumors, but their effects in pediatric cancers have been limited so far. On the other hand, targeting myeloid immune checkpoints, such as CD47-SIPRα, provide the opportunity to enhance antitumor effects of myeloid cells, including that of neutrophils, especially in the presence of cancer-opsonizing antibodies. Disialoganglioside (GD2)-expressing neuroblastoma cells targeted with anti-GD2 antibody dinutuximab are in part eradicated by neutrophils, as they recognize and bind the antibody targeted tumor cells through their Fc receptors. Therapeutic targeting of the innate immune checkpoint CD47-SIRPα has been shown to promote the potential of neutrophils as cytotoxic cells in different solid tumor indications using different cancer-targeting antibodies. Here, we demonstrate that the capacity of neutrophils to kill dinutuximab-opsonized neuroblastoma cells is also controlled by the CD47-SIRPα axis and can be further enhanced by antagonizing CD47-SIRPα interactions. In particular, CD47-SIRPa checkpoint inhibition enhanced neutrophil-mediated ADCC of dinutuximab-opsonized adrenergic neuroblastoma cells, whereas mesenchymal neuroblastoma cells may evade immune recognition by a reduction of GD2 expression. These findings provide a rational basis for targeting CD47-SIRPα interactions to potentiate dinutuximab responsiveness in neuroblastomas with adrenergic phenotype.