A subset analysis of a phase <scp>II</scp> trial evaluating the use of <scp>DFMO</scp> as maintenance therapy for high‐risk neuroblastoma

Lewis, Elizabeth C.; Kraveka, Jacqueline M.; Ferguson, William S.; Eslin, Don; Brown, Valerie I.; Bergendahl, Genevieve; Roberts, William; Wada, Randal K.; Oesterheld, Javier; Mitchell, Deanna; Foley, Jessica; Zage, Peter E.; Rawwas, Jawhar; Rich, Maria; Lorenzi, Elizabeth; Broglio, Kristine; Berry, Donald A.; Sholler, Giselle L. Saulnier

doi:10.1002/ijc.33044

Cited by 44 publications

(38 citation statements)

References 23 publications

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“…Suppression of polyamines, for example, by the inhibition of ODC with α-difluoromethylornithine (DFMO) has been explored as a therapeutic strategy in a variety of cancers including neuroblastoma [ 11 , 12 , 13 , 14 ]. In pediatric neuroblastoma patients, DFMO has been demonstrated to be well tolerated in doses of up to 1500 mg/m 2 twice daily for 21 day cycles as well as for maintenance therapy for two years with a dose of 750 ± 250 mg/m 2 twice daily [ 14 , 15 ]. Administration of DFMO during pregnancy has been correlated to fetal development, namely, the alteration of skeletal variations with high levels of preimplantation issues at high dosage in material water, ranking it as a category C drug [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development

Prokop

Bupp

Frisch

et al. 2021

Genes

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Ornithine decarboxylase 1 (ODC1 gene) has been linked through gain-of-function variants to a rare disease featuring developmental delay, alopecia, macrocephaly, and structural brain anomalies. ODC1 has been linked to additional diseases like cancer, with growing evidence for neurological contributions to schizophrenia, mood disorders, anxiety, epilepsy, learning, and suicidal behavior. The evidence of ODC1 connection to neural disorders highlights the need for a systematic analysis of ODC1 genotype-to-phenotype associations. An analysis of variants from ClinVar, Geno2MP, TOPMed, gnomAD, and COSMIC revealed an intellectual disability and seizure connected loss-of-function variant, ODC G84R (rs138359527, NC_000002.12:g.10444500C > T). The missense variant is found in ~1% of South Asian individuals and results in 2.5-fold decrease in enzyme function. Expression quantitative trait loci (eQTLs) reveal multiple functionally annotated, non-coding variants regulating ODC1 that associate with psychiatric/neurological phenotypes. Further dissection of RNA-Seq during fetal brain development and within cerebral organoids showed an association of ODC1 expression with cell proliferation of neural progenitor cells, suggesting gain-of-function variants with neural over-proliferation and loss-of-function variants with neural depletion. The linkage from the expression data of ODC1 in early neural progenitor proliferation to phenotypes of neurodevelopmental delay and to the connection of polyamine metabolites in brain function establish ODC1 as a bona fide neurodevelopmental disorder gene.

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Section: Introductionmentioning

confidence: 99%

Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development

Prokop

Bupp

Frisch

et al. 2021

Genes

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“…Hypusinilated eIF5A is essential for translation of genes encoding for proteins involved in the cytoskeletal-associated process, RNA splicing and turnover, DNA binding and transcription, and cell signalling [ 232 ]. Notably, ODC1, a key enzyme in polyamine metabolism which converts ornithine to putrescine, is a direct transcription target of N-Myc [ 230 , 233 ]. ODC1 is druggable by difluoromethylornithine (DFMO), which recently completed a phase II clinical trial.…”

Section: Transcriptional Dysregulated Programmes and Promising Therapeutic Approachesmentioning

confidence: 99%

Targeting Oncogenic Transcriptional Networks in Neuroblastoma: From N-Myc to Epigenetic Drugs

Ciaccio

Rosa

Aloisi

et al. 2021

IJMS

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Neuroblastoma (NB) is one of the most frequently occurring neurogenic extracranial solid cancers in childhood and infancy. Over the years, many pieces of evidence suggested that NB development is controlled by gene expression dysregulation. These unleashed programs that outline NB cancer cells make them highly dependent on specific tuning of gene expression, which can act co-operatively to define the differentiation state, cell identity, and specialized functions. The peculiar regulation is mainly caused by genetic and epigenetic alterations, resulting in the dependency on a small set of key master transcriptional regulators as the convergence point of multiple signalling pathways. In this review, we provide a comprehensive blueprint of transcriptional regulation bearing NB initiation and progression, unveiling the complexity of novel oncogenic and tumour suppressive regulatory networks of this pathology. Furthermore, we underline the significance of multi-target therapies against these hallmarks, showing how novel approaches, together with chemotherapy, surgery, or radiotherapy, can have substantial antineoplastic effects, disrupting a wide variety of tumorigenic pathways through combinations of different treatments.

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“…α-difluoromethylornithine (DFMO) is a welltolerated, potent, and irreversible inhibitor of ODC1. Despite its poor pharmacokinetics, DFMO has significant therapeutic potential as a FDA-approved drug for treating trypanosoma (African sleeping sickness) [54], and it also has shown promising results in the on-going clinical trial for treating high-risk neuroblastoma, a severe form of pediatric tumor [ClinicalTrials.gov Identifier: NCT02679144] [55][56][57]. In our studies, DFMO was used as a chemical probe to inhibit ODC1 function and block downstream polyamine synthesis.…”

Section: Inhibition Of Polyamine Synthesis Efficiently Blocks Kshv Lymentioning

confidence: 99%

Polyamine biosynthesis and eIF5A hypusination are modulated by the DNA tumor virus KSHV and promote KSHV viral infection

Fiches

Biswas

Zhou

et al. 2020

Preprint

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Polyamines are critical metabolites involved in various cellular processes and often dysregulated in cancers. Kaposi’s sarcoma associated Herpesvirus (KSHV) is a defined oncogenic virus belonging to the sub-family of human gamma-herpesviruses. KSHV infection leads to the profound alteration of host metabolic landscape to favor the development of KSHV-associated malignancies. In our studies, we identified that polyamine biosynthesis and eIF5A hypusination are dynamically regulated by KSHV infection likely through the modulation of key enzymes of these pathways, such as ODC1, and that in return these metabolic pathways are required for both KSHV lytic switch from latency and de novo infection. The further analysis unraveled that translation of critical KSHV latent and lytic proteins (LANA, RTA) depends on eIF5A hypusination. We also demonstrated that KSHV infection can be efficiently and specifically suppressed by using inhibitors targeting either polyamine biosynthesis or eIF5A hypusination. Above all, our results illustrated that the dynamic and profound interaction of a DNA tumor virus (KSHV) with host polyamine biosynthesis and eIF5A hypusination metabolic pathways promote viral propagation and oncogenesis, which serve as new therapeutic targets to treat KSHV-associated malignancies.

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A subset analysis of a phase II trial evaluating the use of DFMO as maintenance therapy for high‐risk neuroblastoma

Cited by 44 publications

References 23 publications

Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development

Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development

Targeting Oncogenic Transcriptional Networks in Neuroblastoma: From N-Myc to Epigenetic Drugs

Polyamine biosynthesis and eIF5A hypusination are modulated by the DNA tumor virus KSHV and promote KSHV viral infection

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