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Overcoming resistance to anti-VEGF therapy via epigenetic regulation of BARD1 [methylation]

ABSTRACT: Overcoming resistance to anti-VEGF therapy via epigenetic regulation of BARD1 [methylation]

PROVIDER: PRJNA1039888 | ENA |

REPOSITORIES: ENA

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Overcoming resistance to anti-VEGF therapy via epigenetic regulation of BARD1 [OVCAR8ip1 BARD1 overexpression]

Project description:Despite widespread use of anti-vascular endothelial growth factor (VEGF) antibody (AVA) for cancer therapy, most patients develop progressive disease after initial response. Therefore, novel strategies are needed to understand and overcome AVA resistance. Here, we identify an unexpected role of BRCA1-associated RING domain 1 (BARD1) in overcoming adaptive resistance to AVA. We investigated the effects of epigenetic modulation on cellular response to AVA; in particular, the molecular effects of both global and targeted DNA methylation. Using in vitro assays, BARD1 was identified as being specifically involved in angiogenesis. Sequential treatment with azacytidine overcame AVA therapy resistance in cancer models in vivo. We further demonstrated that specifically targeting BARD1 with either small-interfering RNA or CpG-targeted demethylation reduced tumor growth when combined with AVA therapy (compared with AVA alone) in mouse models of ovarian cancer. These results identify a previously unrecognized role for BARD1 in tumor angiogenesis and show that targeted restoration of BARD1 can enhance the efficacy of AVA therapy in cancer models.

2025-06-16 | GSE247653 | GEO

Overcoming resistance to anti-VEGF therapy via epigenetic regulation of BARD1 [BeadChip expression]

2025-06-16 | GSE249415 | GEO

Overcoming resistance to anti-VEGF therapy via epigenetic regulation of BARD1 [SKOV3 BARD1 siRNA-RNASeq]

2025-06-17 | GSE247654 | GEO

Overcoming resistance to anti-VEGF therapy via epigenetic regulation of BARD1

Project description:Overcoming resistance to anti-VEGF therapy via epigenetic regulation of BARD1

| PRJNA1039884 | ENA

Overcoming resistance to anti-VEGF therapy via epigenetic regulation of BARD1 [OVCAR8ip1 BARD1 overexpression]

Project description:Overcoming resistance to anti-VEGF therapy via epigenetic regulation of BARD1 [OVCAR8ip1 BARD1 overexpression]

| PRJNA1039887 | ENA

Overcoming resistance to anti-VEGF therapy via epigenetic regulation of BARD1 [SKOV3 BARD1 siRNA-RNASeq]

Project description:Overcoming resistance to anti-VEGF therapy via epigenetic regulation of BARD1 [SKOV3 BARD1 siRNA-RNASeq]

| PRJNA1039889 | ENA

Overcoming resistance to anti-VEGF therapy via epigenetic regulation of BARD1 [BeadChip expression]

Project description:Overcoming resistance to anti-VEGF therapy via epigenetic regulation of BARD1 [BeadChip expression]

| PRJNA1049004 | ENA

Overcoming resistance to anti-VEGF therapy via epigenetic regulation of BARD1 [methylation]

Project description:Genome wide DNA methylation profiling of anti-VEGF resistant SKOV3 tumor samples treated with B20 and/or Azacytidine. The Illumina Infinium 450k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 450,000 CpGs in SKOV3 tumors. Samples included 2 control IgG, 2 Azacytidine, 2 B20 and 2 B20+Azacytidine treated SKOV3ip1 tumors.

2025-06-17 | GSE247655 | GEO

Overcoming resistance to anti-VEGF therapy via epigenetic regulation of BARD1

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

2025-06-17 | GSE247656 | GEO

Metronomic doxorubicin blocks HIF-1α-mediated responses in sarcomas and augments the effects of anti-VEGF-A therapy

Project description:Increased levels of hypoxia and hypoxia inducible factor 1α (HIF-1α) in human sarcomas correlate with tumor progression and radiation resistance. Prolonged anti-angiogenic therapy of tumors can delay tumor growth but may also increase hypoxia and HIF-1α activity. In our recent clinical trial, treatment with the anti-vascular endothelial growth factor A (VEGF-A) antibody, bevacizumab, followed by a combination of bevacizumab and radiation led to near complete necrosis in nearly half of sarcomas. Gene set enrichment analysis of microarrays from pre-treatment biopsies found the Gene Ontology category “Response to hypoxia” was upregulated in poor responders, and hierarchical clustering based on 140 hypoxia-responsive genes separated poor responders from good responders. The most commonly used chemotherapeutic drug for sarcomas, doxorubicin (Dox), was recently found to block HIF-1α binding to DNA at low metronomic doses. We thus examined Dox treatment in 4 sarcoma cell lines, and found Dox at low concentrations (1-10 uM) blocked HIF-1α induction of VEGF-A by 84-97%, while inhibition of other HIF-1α-target genes including CA9, c-Met and FOXM1 was variable. HT1080 sarcoma xenografts had increased hypoxia and/or HIF-1α activity with increasing tumor size and with anti-VEGF receptor antibody (DC101) treatment. Combining DC101 and metronomic Dox had a synergistic effect in suppressing growth of HT1080 xenografts, primarily via induction of tumor endothelial cell apoptosis. In conclusion, sarcomas respond to increased hypoxia by expressing HIF-1α-target genes which may promote resistance to anti-angiogenic and other therapies. Metronomic Dox can block HIF-1α activation of target genes and works synergistically with anti-VEGF therapy to inhibit sarcomas. Pre-treatment biopsies were collected from 16 human sarcoma. The gene expression analysis was performed using Illumina platform.

2011-08-29 | E-GEOD-31715 | biostudies-arrayexpress

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