Understanding and therapeutically targeting oncogenic chromatin biology in childhood cancers

During his PhD at Trinity College Dublin Gerry worked on understanding fundamental mechanisms of chromatin regulation, with a particular focus on the Polycomb group of transcriptional repressors. Here, he discovered a new member of the Polycomb Repressive Complex 2 (PRC2) and attributed specific functions to complexes containing this protein. Following his PhD, Gerry pursued post-doctoral work initially at the Memorial Sloan Kettering Cancer Center in New York, and subsequently at the Dana Farber Cancer Institute and Harvard Medical School in Boston. During this time he was focused on using functional genomics and chemical biology based approaches to identify therapeutic vulnerabilities in childhood cancers. This led to the identification of the chromatin regulator BRD9 as a specific functional dependency in synovial sarcoma tumour cells. This vulnerability was exploited through the development of novel small-molecule protein degrader drugs targeting BRD9; with 2 related drugs now in clinical trials. Since returning to Ireland, Gerry has established his own research group at Trinity College Dublin. His research program combines expertise in chromatin biology, functional genomics and chemical biology to study the oncogenic chromatic regulatory processes that underpin cancer associated gene expression programs. Discoveries made are guiding the development of mechanistically anchored disease therapeutics disrupting these processes in childhood cancers.

Key Publications:

Simultaneous disruption of PRC2 and enhancer function underlies histone H3.3-K27M oncogenic activity in human hindbrain neural stem cells.

Brien GL, Bressan RB, Monger C, Gannon D, Lagan E, Doherty AM, Healy E, Neikes H, Fitzpatrick DJ, Deevy O, Grant V, Marqués-Torrejón MA, Alfazema N, Pollard SM, Bracken AP. Nature Genetics 53, 1221-1232 2021.

Targeting chromatin complexes in fusion protein-driven malignancies.

Brien GL, Stegmaier K, Armstrong SA. Nature Reviews Cancer 2019 May 19(5):255-269.

Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma.

Brien GL, Remillard D, Shi J, Hemming ML, Chabon J, Wynne K, Dillon ET, Cagney G, Van Mierlo G, Baltiseen MP, Vermeulen M, Qi J, Frohling S, Gray NS, Bradner JE, Vakoc CR, Armstrong SA. Elife 2018 Nov 15;7 10.7554/eLife.41305.

Exploiting the epigenome to control cancer promoting gene expression programs.

Brien GL, Valerio DG, Armstrong SA. Cancer Cell. 2016 Apr 11;29(4):464-476.

Polycomb PHF19 binds H3K26me3 and recruits PRC2 and demethylase NO66 to embryonic stem cell genes during differentiation.

Brien GL, Gambero G, O’Connell DJ, Jerman E, Turner SA, Egan CM, Dunne EJ, Jurgens MC, Wynne K, Piao L, Lohan AJ, Ferguson N, Shi X, Sinha KM, Loftus BJ, Cagney G, Bracken AP. Nature Structural & Molecular Biology. 2012 Dec;19(12):1273-81.