Therapeutic Targeting of Non-oncogene Dependencies in High-risk Neuroblastoma

Huang, Chen; Hsieh, Chiao; Lee, Wen Chi; Liu, Yen‐Lin; Yang, Tsai Shan; Hsu, Wen Ming; Oyang, Yen Jen; Huang, Hsuan Cheng; Juan, Hsueh Fen

doi:10.1158/1078-0432.ccr-18-4117

Cited by 15 publications

(10 citation statements)

References 70 publications

(80 reference statements)

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“…Anti-metabolic agents have been used in cancer treatment for decades, however, a relatively low number of metabolic inhibitors developed for cancer therapy due to the adverse effects on patients by blocking the synthesis of vital cellular constituents from metabolic pathways 41 . Our strategy for identifying anti-cancer agents is to screen for compounds that particularly target MYCN-regulated metabolic genes across cell lines by using transcriptomic profiles 31,32 . By matching gene signatures with drug signatures, we systematically identified the gene expressions of MTHFD2 and PAICS were significantly suppressed by anisomycin and apicidin across ten cell lines (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Perturbation datasets corresponding to the treatment of various drugs or compounds for ten cell lines, including A375, A549, HA1E, HCC515, HEPG2, HT29, MCF7, NPC, PC3, and VCAP, were obtained from the Library of Integrated Network-based Cellular Signatures (LINCS) project 30 . To identify the compounds that significantly suppress the gene expressions of MTHFD2 and PAICS based on the perturbation datasets, computational approach was performed as detailed in our previous methods 31,32 . Briefly, the expression changes of all measured transcripts ( n = 12,494) were ordered from the most downregulated (negative) to the most upregulated (positive) cross ten cell lines and assessed if the gene of interest was significantly enriched on the down-regulation edge cross all cell types under the perturbation of the given compound.…”

Section: Methodsmentioning

confidence: 99%

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Combinatorial targeting of MTHFD2 and PAICS in purine synthesis as a novel therapeutic strategy

et al. 2019

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MYCN-amplified (MNA) neuroblastoma is an aggressive neural crest-derived pediatric cancer. However, MYCN is indispensable for development and transcriptionally regulates extensive network of genes. Integrating anti-MYCN ChIP-seq and gene expression profiles of neuroblastoma patients revealed the metabolic enzymes, MTHFD2 and PAICS, required for one-carbon metabolism and purine biosynthesis were concomitantly upregulated, which were more susceptible to metastatic neuroblastoma. Moreover, we found that MYCN mediated the folate cycle via MTHFD2, which contributed one-carbon unit to enhance purine synthesis, and further regulated nucleotide production by PAICS in response to cancer progression. Dual knockdown of the MYCN-targeted gene pair, MTHFD2 and PAICS, in MNA neuroblastoma cells synergically reduced cell proliferation, colony formation, migration ability, and DNA synthesis. By systematically screening the compound perturbagens, the gene expression levels of MTHFD2 and PAICS were specifically suppressed by anisomycin and apicidin across cell lines, and our co-treatment results also displayed synergistic inhibition of MNA neuroblastoma cell proliferation. Collectively, targeting a combination of MYCN-targeted genes that interrupts the interconnection of metabolic pathways may overcome drug toxicity and improve the efficacy of current therapeutic agents in MNA neuroblastoma.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Combinatorial targeting of MTHFD2 and PAICS in purine synthesis as a novel therapeutic strategy

et al. 2019

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“…Thanks to the development of microarrays and high-throughput technologies, an increasing number of abnormalities have been discovered in both driver and non-driver genes in NB ( 7 ). Unlike adult cancers, the total somatic mutation rate is less than 20%, even in the high risk NB, as reported by a study from TARGET enrolling 240 patients.…”

Section: Introductionmentioning

confidence: 99%

Prognostic Signature of Immune Genes and Immune-Related LncRNAs in Neuroblastoma: A Study Based on GEO and TARGET Datasets

et al. 2021

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BackgroundThe prognostic value of immune-related genes and lncRNAs in neuroblastoma has not been elucidated, especially in subgroups with different outcomes. This study aimed to explore immune-related prognostic signatures.Materials and MethodsImmune-related prognostic genes and lncRNAs were identified by univariate Cox regression analysis in the training set. The top 20 C-index genes and 17 immune-related lncRNAs were included in prognostic model construction, and random forest and the Least Absolute Shrinkage and Selection Operator (LASSO) regression algorithms were employed to select features. The risk score model was constructed and assessed using the Kaplan-Meier plot and the receiver operating characteristic curve. Functional enrichment analysis of the immune-related lncRNAs was conducted using the STRING database.ResultsIn GSE49710, five immune genes (CDK4, PIK3R1, THRA, MAP2K2, and ULBP2) were included in the risk score five genes (RS5_G) signature, and eleven immune-related lncRNAs (LINC00260, FAM13A1OS, AGPAT4-IT1, DUBR, MIAT, TSC22D1-AS1, DANCR, MIR137HG, ERC2-IT1, LINC01184, LINC00667) were brought into risk score LncRNAs (RS_Lnc) signature. Patients were divided into high/low-risk score groups by the median. Overall survival and event/progression-free survival time were shortened in patients with high scores, both in training and validation cohorts. The same results were found in subgroups. In grouping ability assessment, the area under the curves (AUCs) in distinguishing different groups ranged from 0.737 to 0.94, better in discriminating MYCN status and high risk in training cohort (higher than 0.9). Multivariate Cox analysis demonstrated that RS5_G and RS_Lnc were the independent risk factors for overall and event/progression-free survival (all p-values <0.001). Correlation analysis showed that RS5_G and RS_Lnc were negatively associated with aDC, CD8+ T cells, but positively correlated with Th2 cells. Functional enrichment analyzes demonstrated that immune-related lncRNAs are mainly enriched in cancer-related pathways and immune-related pathways.ConclusionWe identified the immune-related prognostic signature RS5_G and RS_Lnc. The predicting and grouping ability is close to being even better than those reported in other studies, especially in subgroups. This study provided prognostic signatures that may help clinicians to choose optimal treatment strategies and showed a new insight for NB treatment. These results need further biological experiments and clinical validation.

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“…(105)(106)(107)(108)(109). Due to the possibility of targeting quite different communication fluxes in tumor systems with well-tuned combinations of master modifiers, pro-anakoinotic therapies may induce multifold biological and clinical readouts, as shown in…”

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confidence: 99%

Anakoinosis: Correcting Aberrant Homeostasis of Cancer Tissue—Going Beyond Apoptosis Induction

et al. 2019

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The current approach to systemic therapy for metastatic cancer is aimed predominantly at inducing apoptosis of cancer cells by blocking tumor-promoting signaling pathways or by eradicating cell compartments within the tumor. In contrast, a systems view of therapy primarily considers the communication protocols that exist at multiple levels within the tumor complex, and the role of key regulators of such systems. Such regulators may have far-reaching influence on tumor response to therapy and therefore patient survival. This implies that neoplasia may be considered as a cell non-autonomous disease. The multi-scale activity ranges from intra-tumor cell compartments, to the tumor, to the tumor-harboring organ to the organism. In contrast to molecularly targeted therapies, a systems approach that identifies the complex communications networks driving tumor growth offers the prospect of disrupting or "normalizing" such aberrant communicative behaviors and therefore attenuating tumor growth. Communicative reprogramming, a treatment strategy referred to as anakoinosis, requires novel therapeutic instruments, so-called master modifiers to deliver concerted tumor growth-attenuating action. The diversity of biological outcomes following pro-anakoinotic tumor therapy, such as differentiation, trans-differentiation, control of tumor-associated inflammation, etc. demonstrates that long-term tumor control may occur in multiple forms, inducing even continuous complete remission. Accordingly, pro-anakoinotic therapies dramatically extend the repertoire for achieving tumor control and may activate apoptosis pathways for controlling resistant metastatic tumor disease and hematologic neoplasia.

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Therapeutic Targeting of Non-oncogene Dependencies in High-risk Neuroblastoma

Cited by 15 publications

References 70 publications

Combinatorial targeting of MTHFD2 and PAICS in purine synthesis as a novel therapeutic strategy

Combinatorial targeting of MTHFD2 and PAICS in purine synthesis as a novel therapeutic strategy

Prognostic Signature of Immune Genes and Immune-Related LncRNAs in Neuroblastoma: A Study Based on GEO and TARGET Datasets

Anakoinosis: Correcting Aberrant Homeostasis of Cancer Tissue—Going Beyond Apoptosis Induction

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