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Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE214803 | GEO | 2022/11/09

REPOSITORIES: GEO

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Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma [EPIC]

Project description:MYC-driven medulloblastoma (MB) is an aggressive pediatric brain tumor characterized by therapy resistance and disease recurrence. Here we integrated data from unbiased genetic screening and metabolomic profiling to identify multiple cancer-selective metabolic vulnerabilities in MYC-driven MB tumor cells, which are amenable to therapeutic targeting. Among these targets, dihydroorotate dehydrogenase (DHODH), an enzyme that catalyzes de novo pyrimidine biosynthesis, emerged as a favorable candidate for therapeutic targeting. Mechanistically, DHODH inhibition acts on-target leading to uridine metabolite scarcity and hyperlipidemia, accompanied by reduced protein O-GlcNAcylation and c-Myc degradation. Pyrimidine starvation evokes a metabolic stress response that leads to cell cycle arrest and apoptosis. We further show that an orally available small molecule DHODH inhibitor demonstrates potent mono-therapeutic efficacy against patient-derived MB xenografts in vivo. The reprogramming of pyrimidine metabolism in MYC-driven medulloblastoma represents an unappreciated therapeutic strategy and a potential new class of treatments with stronger cancer selectivity and fewer neurotoxic sequelae.

2022-11-09 | GSE214802 | GEO

Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma. [CRISPRseq]

2022-11-09 | GSE214956 | GEO

Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma [RNA-seq]

2022-11-09 | GSE214801 | GEO

Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma

Project description:Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma

| PRJNA887081 | ENA

Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma. [CRISPRseq]

Project description:Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma. [CRISPRseq]

| PRJNA887789 | ENA

Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma [EPIC]

Project description:Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma [EPIC]

| PRJNA887097 | ENA

Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma [RNA-seq]

Project description:Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma [RNA-seq]

| PRJNA887094 | ENA

Functional Genomics Identifies Metabolic Vulnerabilities in Pancreatic Cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-10-01 | GSE158787 | GEO

BET bromodomain inhibition of MYC-amplified medulloblastoma.

Project description:PURPOSE:MYC-amplified medulloblastomas are highly lethal tumors. Bromodomain and extraterminal (BET) bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here, we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma. EXPERIMENTAL DESIGN:We evaluated the effects of genetic and pharmacologic inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and genetically engineered mouse model (GEMM)-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC or MYCN. We also assessed the effect of JQ1 on MYC expression and global MYC-associated transcriptional activity. We assessed the in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice. RESULTS:Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G1 and apoptosis. We observed downregulation of MYC expression and confirmed the inhibition of MYC-associated transcriptional targets. The exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged the survival of orthotopic xenograft models of MYC-amplified medulloblastoma (P < 0.001). Xenografts harvested from mice after five doses of JQ1 had reduced the expression of MYC mRNA and a reduced proliferative index. CONCLUSION:JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma.

| S-EPMC4198154 | biostudies-literature

Metabolic adaptations underlie epigenetic vulnerabilities in chemoresistant breast cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-08-18 | GSE113687 | GEO