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Integrated Metabolic Profiling and Gene Expression Analysis Reveals Therapeutic Modalities in Breast Cancer

ABSTRACT: Integrated Metabolic Profiling and Gene Expression Analysis Reveals Therapeutic Modalities in Breast Cancer

PROVIDER: PRJNA727822 | ENA |

REPOSITORIES: ENA

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Integrated Metabolic Profiling and Gene Expression Analysis Reveals Therapeutic Modalities in Breast Cancer

Project description:Integrated Metabolic Profiling and Gene Expression Analysis Reveals Therapeutic Modalities in Breast Cancer

| PRJNA720180 | ENA

Integrated Metabolic Profiling and Gene Expression Analysis Reveals Therapeutic Modalities in Breast Cancer

Project description:Integrated Metabolic Profiling and Gene Expression Analysis Reveals Therapeutic Modalities in Breast Cancer

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Integrated Metabolic Profiling and Gene Expression Analysis Reveals Therapeutic Modalities in Breast Cancer

Project description:Here, we report two distinctive groups defined by metabolites; a TNBC-HIGH group that shows high levels of pyrimidine pathway metabolites and biosynthetic enzymes, and an ER-HIGH group that shows high levels of fatty acid and arginine biosynthesis intermediates. We identify different metabolic enrichment profiles between cell lines grown in vitro vs. in vivo; cell lines grown in vivo recapitulate patient tumors metabolic profiles. Further, we identify a subset of genes that strongly correlates with the TNBC-HIGH metabolic profile using integrated metabolic and gene expression profiling, which strongly predicts patient prognosis when tested on larger human datasets. As a proof-of-principle, when we target TNBC-HIGH metabolic dysregulation with a pyrimidine biosynthesis inhibitor (Brequinar), and/or a glutaminase inhibitor (CB-839), we observe therapeutic efficacy and decreased tumor growth in representative TNBC cell lines, murine p53-null mammary tumors, and in vivo patient-derived xenografts (PDXs) upon multi-agent drug treatment. This study highlights potential new therapeutic opportunities in breast cancers guided by a genomic biomarker, which could prove impactful for breast cancers that rapidly proliferate.

2022-04-27 | GSE173991 | GEO

Integrated Metabolic Profiling and Transcriptional Analysis Reveals Therapeutic Modalities for Targeting Rapidly Proliferating Breast Cancers.

Project description:Metabolic dysregulation is a prominent feature in breast cancer, but it remains poorly characterized in patient tumors. In this study, untargeted metabolomics analysis of triple-negative breast cancer (TNBC) and patient with estrogen receptor (ER)-positive breast cancer samples, as well as TNBC patient-derived xenografts (PDX), revealed two major metabolic groups independent of breast cancer histologic subtypes: a "Nucleotide/Carbohydrate-Enriched" group and a "Lipid/Fatty Acid-Enriched" group. Cell lines grown in vivo more faithfully recapitulated the metabolic profiles of patient tumors compared with those grown in vitro. Integrated metabolic and gene expression analyses identified genes that strongly correlate with metabolic dysregulation and predict patient prognosis. As a proof of principle, targeting Nucleotide/Carbohydrate-Enriched TNBC cell lines or PDX xenografts with a pyrimidine biosynthesis inhibitor or a glutaminase inhibitor led to therapeutic efficacy. In multiple in vivo models of TNBC, treatment with the pyrimidine biosynthesis inhibitor conferred better therapeutic outcomes than chemotherapeutic agents. This study provides a metabolic stratification of breast tumor samples that can guide the selection of effective therapeutic strategies targeting breast cancer subsets. In addition, we have developed a public, interactive data visualization portal (http://brcametab.org) based on the data generated from this study to facilitate future research.SignificanceA multiomics strategy that integrates metabolic and gene expression profiling in patient tumor samples and animal models identifies effective pharmacologic approaches to target rapidly proliferating breast tumor subtypes.

| S-EPMC8857046 | biostudies-literature

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Project description:Childhood Posterior Fossa-A ependymomas (PFAs) have limited treatment options. Integrated metabolic/epigenetic analyses performed to discover therapeutic targets in PFAs demonstrated enhanced glycolysis and TCA-cycle metabolism. PFAs exhibit low H3K27me3, as in H3K27M gliomas. Therefore, we subjected them to panobinostat which kills H3K27M cells, along with the metabolic inhibitor metformin. Combined treatment increased H3K27me3, suppressed metabolism and demonstrated potent therapeutic efficacy in vitro and in vivo, suggesting promising therapeutic strategies.

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Integrated analysis of transcriptional and metabolic responses to mitochondrial stress

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