Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuroblastoma (NB), an embryonal tumor derived from the neural crest, originates from sympathetic nerve system, manifests as thoracic, paraspinous or abdominal tumors, and metastases to bone in high-risk cases. Although NB stands as the most common solid tumor in early childhood and accounts for about 15% of total pediatric cancer death, there has been limited success in searching for novel therapeutic regimen for this lethal disease during the past two decades. Numerous epidemiological and clinical studies have pinpointed anaplastic lymphoma kinase (ALK) and MYCN as potent governors for NB malignant behavior. ALK and MYCN amplification and constitutive active mutations are common in high-risk NB patients. However, there is still lack of evidence showing that a small molecule compound could simultaneously inhibits ALK and MYCN and plays strong negative regulatory roles in NB. Here, we showed that 17-DMAG, a well-known HSP-90 inhibitor, significantly inhibits NB cell growth, arrests cell cycle, and strongly induces NB cell apoptosis. Interestingly, our data suggests that NB cells with both ALK and MYCN amplification/mutation are more sensitive to 17-DMAG treatment, while NB cells with only ALK or MYCN amplification are less sensitive and NB cells without ALK or MYCN amplification/mutation are least sensitive. Moreover, we also found that knocking down ALK and MYCN additively inhibits NB cell growth and that transduction of MYCN largely abolished the ALK-dependent NB cell growth, indicating that there is a cross-talk between MYCN and ALK signaling machinery. Our results provide proof-of-principle that 17-DMAG strongly inhibits NB cell growth by targeting both ALK and MYCN. Our findings might shed a light for further investigation of novel small molecule compound which is safe and exerts similar strong effects in vivo as novel approaches for management of high-risk NB.
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PMID:The growth inhibitory effect of 17-DMAG on ALK and MYCN double-positive neuroblastoma cell line. 2429 93

Receptor tyrosine kinases have emerged as promising therapeutic targets for a diverse set of tumors. Overactivation of the tyrosine kinase anaplastic lymphoma kinase (ALK) has been reported in several types of malignancies such as anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, neuroblastoma, and non-small-cell lung carcinoma. Further characterization of the molecular role of ALK has revealed an oncogenic signaling signature that results in tumor dependence on ALK. ALK-positive tumors display a different behavior than their ALK-negative counterparts; however, the specific role of ALK in some of these tumors remains to be elucidated. Although more studies are required to establish selective targeting of ALK as a definitive therapeutic option, initial trials have shown extraordinary results in the majority of cases.
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PMID:ALK-driven tumors and targeted therapy: focus on crizotinib. 2471 63

Neuroblastomas harbor mutations in the nonreceptor anaplastic lymphoma kinase (ALK) in 8% to 9% of cases where they serve as oncogenic drivers. Strategies to reduce ALK activity offer clinical interest based on initial findings with ALK kinase inhibitors. In this study, we characterized phosphotyrosine-containing proteins associated with ALK to gain mechanistic insights in this setting. Flotillin-1 (FLOT1), a plasma membrane protein involved in endocytosis, was identified as a binding partner of ALK. RNAi-mediated attenuation of FLOT1 expression in neuroblastoma cells caused ALK dissociation from endosomes along with membrane accumulation of ALK, thereby triggering activation of ALK and downstream effector signals. These features enhanced the malignant properties of neuroblastoma cells in vitro and in vivo. Conversely, oncogenic ALK mutants showed less binding affinity to FLOT1 than wild-type ALK. Clinically, lower expression levels of FLOT1 were documented in highly malignant subgroups of human neuroblastoma specimens. Taken together, our findings suggest that attenuation of FLOT1-ALK binding drives malignant phenotypes of neuroblastoma by activating ALK signaling.
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PMID:Flotillin-1 regulates oncogenic signaling in neuroblastoma cells by regulating ALK membrane association. 2483 Jul 26

The anaplastic lymphoma kinase (ALK) gene is overexpressed, mutated or amplified in most neuroblastoma (NB), a pediatric neural crest-derived embryonal tumor. The two most frequent mutations, ALK-F1174L and ALK-R1275Q, contribute to NB tumorigenesis in mouse models, and cooperate with MYCN in the oncogenic process. However, the precise role of activating ALK mutations or ALK-wt overexpression in NB tumor initiation needs further clarification. Human ALK-wt, ALK-F1174L, or ALK-R1275Q were stably expressed in murine neural crest progenitor cells (NCPC), MONC-1 or JoMa1, immortalized with v-Myc or Tamoxifen-inducible Myc-ERT, respectively. While orthotopic implantations of MONC- 1 parental cells in nude mice generated various tumor types, such as NB, osteo/ chondrosarcoma, and undifferentiated tumors, due to v-Myc oncogenic activity, MONC-1-ALK-F1174L cells only produced undifferentiated tumors. Furthermore, our data represent the first demonstration of ALK-wt transforming capacity, as ALK-wt expression in JoMa1 cells, likewise ALK-F1174L, or ALK-R1275Q, in absence of exogenous Myc-ERT activity, was sufficient to induce the formation of aggressive and undifferentiated neural crest cell-derived tumors, but not to drive NB development. Interestingly, JoMa1-ALK tumors and their derived cell lines upregulated Myc endogenous expression, resulting from ALK activation, and both ALK and Myc activities were necessary to confer tumorigenic properties on tumor-derived JoMa1 cells in vitro.
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PMID:Wild-type ALK and activating ALK-R1275Q and ALK-F1174L mutations upregulate Myc and initiate tumor formation in murine neural crest progenitor cells. 2494 26

The gene expressing the receptor tyrosine kinase anaplastic lymphoma kinase (ALK) is mutated and aberrantly expressed in several cancers. The clinical efficacy of the ALK inhibitor, crizotinib, lags behind expectations for treating MYCN-amplified, ALK-mutant neuroblastoma, a deadly childhood cancer. In this issue of Science Signaling, Umapathy et al. identify the kinase extracellular signal-regulated kinase 5 (ERK5) as a central mediator that enables ALK to boost MYCN expression, and they show that inhibiting ERK5 in concert with ALK reduced neuroblastoma cell viability in vitro and in xenograft tumor models. This report has important clinical implications for the treatment of patients with neuroblastoma or other tumors that overexpress MYC(N) and harbor ALK mutations, such as non-small-cell lung cancer.
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PMID:ALK pERKs up MYCN in neuroblastoma. 2535 Dec 46

Genetic studies have established anaplastic lymphoma kinase (ALK), a cell surface receptor tyrosine kinase, as a tractable molecular target in neuroblastoma. We describe comprehensive genomic, biochemical, and computational analyses of ALK mutations across 1,596 diagnostic neuroblastoma samples. ALK tyrosine kinase domain mutations occurred in 8% of samples--at three hot spots and 13 minor sites--and correlated significantly with poorer survival in high- and intermediate-risk neuroblastoma. Biochemical and computational studies distinguished oncogenic (constitutively activating) from nononcogenic mutations and allowed robust computational prediction of their effects. The mutated variants also showed differential in vitro crizotinib sensitivities. Our studies identify ALK genomic status as a clinically important therapeutic stratification tool in neuroblastoma and will allow tailoring of ALK-targeted therapy to specific mutations.
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PMID:ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma. 2551 49

Twenty years ago anaplastic lymphoma kinase (ALK) was discovered in anaplastic large cell lymphoma (ALCL), but the interest in ALK as an oncogene grew only in recent years when ALK rearrangements were reported as recurrent genetic lesions in lung carcinoma and activating single point mutations were described in neuroblastoma. In this review we will describe the main features of ALK-rearranged solid tumors, with particular emphasis to NSCLC and neuroblastoma. We will discuss the numerous in vitro and in vivo studies that confirmed ALK as the driver oncogene in these tumors and the achievements in clinical settings with ALK inhibitors that validated ALK as a therapeutic target. We will finally end with the description of putative innovative therapeutic approaches that are on going to overcome acquired resistance that invariably occurs in crizotinib treated NSCLC patients or intrinsic resistance to crizotinb therapy reported in neuroblastoma.
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PMID:The anaplastic lymphoma kinase as an oncogene in solid tumors. 2596 2

The anaplastic lymphoma kinase (ALK) receptor tyrosine kinase was initially discovered as a component of the fusion protein nucleophosmin (NPM)-ALK in anaplastic large-cell lymphoma (ALCL). Genomic alterations in ALK, including rearrangements, point mutations, and genomic amplification, have now been identified in several malignancies, including lymphoma, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, and others. Importantly, ALK serves as a validated therapeutic target in these diseases. Several ALK tyrosine kinase inhibitors (TKI), including crizotinib, ceritinib, and alectinib, have been developed, and some of them have already been approved for clinical use. These ALK inhibitors have all shown remarkable clinical outcomes in ALK-rearranged NSCLC. Unfortunately, as is the case for other kinase inhibitors in clinical use, sensitive tumors inevitably relapse due to acquired resistance. This review focuses on the discovery, function, and therapeutic targeting of ALK, with a particular focus on ALK-rearranged NSCLC.
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PMID:Therapeutic targeting of anaplastic lymphoma kinase in lung cancer: a paradigm for precision cancer medicine. 2597 29

Alcohol engages signaling pathways in the brain. Midkine (MDK) is a neurotrophic factor that is over-expressed in the prefrontal cortex of alcoholics. MDK and one of its receptors, anaplastic lymphoma kinase (ALK), also regulate behavioral responses to ethanol in mice. The goal of this study was to determine whether MDK and ALK expression and signaling are activated by ethanol. We found that ethanol treatment of neuroblastoma cells increased MDK and ALK expression. We also assessed activation of ALK by ethanol in cells and found that ALK and ALK-dependent extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription 3 (STAT3) phosphorylation increased rapidly with ethanol exposure. Similarly, treatment of cells with recombinant MDK protein increased ALK, ERK and STAT3 phosphorylation, suggesting that ethanol may utilize MDK to activate ALK signaling. In support of this, transfection of cells with MDK siRNAs attenuated ALK signaling in response to ethanol. Ethanol also activates ERK signaling in the brain. We found that inhibition of ALK or knockout of MDK attenuated ethanol-induced ERK phosphorylation in mouse amygdala. These results demonstrate that ethanol engages MDK and ALK signaling, which has important consequences for alcohol-induced neurotoxicity and the regulation of behaviors related to alcohol abuse.
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PMID:Ethanol activates midkine and anaplastic lymphoma kinase signaling in neuroblastoma cells and in the brain. 2620 65

Bellini and colleagues demonstrate the importance of next-generation sequencing to uncover subclonal anaplastic lymphoma kinase (ALK) mutations in neuroblastoma. Although the significance of these subclonal aberrations is not yet understood, deep sequencing could identify patients whose tumors may respond to ALK inhibitors.
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PMID:Seek and Ye Shall Find: Subclonal Anaplastic Lymphoma Kinase Mutations. 2605 87


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