Therapies that abrogate persistent androgen receptor (AR) signaling in castration resistant prostate cancer (CRPC) remain an unmet clinical need. The N-terminal domain (NTD) of the AR that drives transcriptional activity in CRPC remains a challenging therapeutic target. Herein we demonstrate that BAG-1 mRNA is highly expressed and associates with signaling pathways, including AR signaling, that are implicated in the development and progression of CRPC. In addition, interrogation of geometric and physiochemical properties of the BAG domain of BAG-1 isoforms identifies it to be a tractable but challenging drug target. Furthermore, through BAG-1 isoform mouse knockout studies we confirm that BAG-1 isoforms regulate hormone physiology and that therapies targeting the BAG domain will be associated with limited 'on-target' toxicity. Importantly, the postulated inhibitor of BAG-1 isoforms, Thio-2, suppressed AR signaling and other important pathways implicated in the development and progression of CRPC to reduce the growth of treatment resistant prostate cancer cell lines and patient derived models. However, the mechanism by which Thio-2 elicits the observed phenotype needs further elucidation since the genomic abrogation of BAG-1 isoforms was unable to recapitulate the Thio-2 mediated phenotype. Overall, these data support the interrogation of related compounds with improved drug-like properties as a novel therapeutic approach in CRPC, and further highlight the clinical potential of treatments that block persistent AR signaling which are currently undergoing clinical evaluation in CRPC.
Molecular cancer therapeutics. 2024 Feb 27 [Epub ahead of print]
Antje Neeb, Ines Figueiredo, Denisa Bogdan, Laura Cato, Jutta Stober, Juan M Jiménez-Vacas, Victor Gourain, Irene I Lee, Rebecca Seeger, Claudia Muhle-Goll, Bora Gurel, Jonathan Welti, Daniel Nava Rodrigues, Jan Rekowski, Xintao Qiu, Yija Jiang, Patrizio Di Micco, Borja Mateos, Stasė Bielskutė, Ruth Riisnaes, Ana Ferreira, Susana Miranda, Mateus Crespo, Lorenzo Buroni, Jian Ning, Suzanne Carreira, Stefan Bräse, Nicole Jung, Simone Gräßle, Amanda Swain, Xavier Salvatella, Stephen R Plymate, Bissan Al-Lazikani, Henry W Long, Wei Yuan, Myles Brown, Andrew C B Cato, Johann S de Bono, Adam Sharp
Institute of Cancer Research, Surrey, United Kingdom., Institute of Cancer Research, Sutton, Surrey, United Kingdom., Institute of Cancer Research, London, United Kingdom., Dana-Farber Cancer Institute, Boston, MA, United States., Karlsruhe Institute of Technology, Germany., Nantes University, Nantes, France., AbbVie (United States), North Chicago, IL, United States., Dana-Farber Cancer Institute, United States., Institute of Biomedical Research of Barcelona, Spain., Institute for Research in Biomedicine, Spain., Institute of Cancer Research, Sutton, United Kingdom., KIT Campus South, Institute of Organic Chemistry, Karlsruhe, Germany., Karlsruhe Institute of Technology, Karlsruhe, Germany., Karlsruhe Institute of Technology (KIT), Karlsruhe, Eggenstein-Leopoldshafen, Germany., Institute for Research in Biomedicine, Barcelona, Spain., University of Washington, Seattle, Washington, United States., Institute of Cancer Research, Houston, TX, United States., Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany.