Epigenetic modulation of BARD1 to enhance anti-VEGF therapy
Despite the clinical use of anti-vascular endothelial growth factor (VEGF) antibodies (AVAs) in cancer therapy, resistance frequently develops, leading to disease progression. To address this, we identify a previously unknown role for breast cancer type 1 susceptibility protein (BRCA1)-associated RING domain 1 (BARD1) in modulating AVA sensitivity. Epigenetic modulation-via global and targeted DNA methylation-reveals BARD1 as a key regulator of angiogenesis. Sequential treatment with azacytidine overcomes AVA resistance in vivo. To enable precise epigenetic reactivation, we develop a liposomal CRISPR-deactivated Cas9 (dCas9)-TET1 system guided by BARD1-targeting single-guide RNAs (sgRNAs). This platform achieves CpG-specific demethylation of the BARD1 promoter, restores expression, and enhances AVA response. Additionally, BARD1 restoration, through either dCas9-TET1 or small interfering RNA (siRNA), significantly reduces tumor growth in combination with AVA in ovarian cancer models. These findings uncover a previously unrecognized function of BARD1 in tumor angiogenesis and demonstrate the potential of gene-specific epigenetic targeting to overcome AVA resistance.
Authors
- Abhinav K. Jain (ORCID: https://orcid.org/0000-0003-3268-514X)
- Sudhir Kumar (ORCID: https://orcid.org/0000-0001-5806-3029)
- Emine Bayraktar (ORCID: https://orcid.org/0000-0002-5189-1507)
- Gabriel Lopez‐Berestein
- Adrian Lankenau Ahumada (ORCID: https://orcid.org/0000-0002-1490-7311)
- Mark S. Kim (ORCID: https://orcid.org/0000-0003-1959-3259)
- Cristian Rodriguez-Aguayo
- Sara Corvigno (ORCID: https://orcid.org/0000-0001-5458-2243)
- Marcos R. Estecio (ORCID: https://orcid.org/0000-0002-6874-7413)
- Weisen Wu (ORCID: https://orcid.org/0009-0002-4701-8948)
- Stephen Baylin
- Lingegowda S. Mangala
- John P. Hagan (ORCID: https://orcid.org/0000-0003-0295-4898)
- Sunila Pradeep
- Nazende Nur Bayram (ORCID: https://orcid.org/0000-0002-8697-1654)
- Elaine Stur (ORCID: https://orcid.org/0000-0001-5962-0050)
- Hülya Öztatlıcı (ORCID: https://orcid.org/0000-0002-6749-9665)
- Pahul Hanjra (ORCID: https://orcid.org/0000-0002-7705-7967)
- Nidhi Sahni (ORCID: https://orcid.org/0000-0002-9155-5882)
- Ju‐Seog Lee (ORCID: https://orcid.org/0000-0002-5666-9753)
- Cristina Ivan
- Jinsong Liu (ORCID: https://orcid.org/0000-0002-3239-6658)
- Thanh Chung Vu (ORCID: https://orcid.org/0000-0002-8770-1269)
- Anna Szymanowska (ORCID: https://orcid.org/0000-0003-4783-3336)
- Sanghoon Lee (ORCID: https://orcid.org/0000-0002-1265-3821)
- Anil K. Sood (ORCID: https://orcid.org/0000-0003-4242-1762)
- Sangbae Kim
- Nicholas B. Jennings (ORCID: https://orcid.org/0000-0003-0357-2920)
- Amma Asare
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- Johns Hopkins University (US)
- Baylor College of Medicine (US)
- Medical College of Wisconsin (US)
- Baylor Genetics (US)
- Sidney Kimmel Comprehensive Cancer Center (US)
- The University of Texas Health Science Center at Houston (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-09-01
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102329
- Citations
- 2
- Primary Topic
- CRISPR and Genetic Engineering
- Type
- article
- Field-Weighted Citation Impact
- 1.61