Journal article
Co-targeting BET, CBP, and p300 inhibits neuroendocrine signalling in androgen receptor-null prostate cancer
N Choo, S Keerthikumar, S Ramm, D Ashikari, L Teng, B Niranjan, S Hedwards, LH Porter, DL Goode, KJ Simpson, RA Taylor, GP Risbridger, MG Lawrence
Journal of Pathology | Published : 2024
DOI: 10.1002/path.6280
Abstract
There are diverse phenotypes of castration-resistant prostate cancer, including neuroendocrine disease, that vary in their sensitivity to drug treatment. The efficacy of BET and CBP/p300 inhibitors in prostate cancer is attributed, at least in part, to their ability to decrease androgen receptor (AR) signalling. However, the activity of BET and CBP/p300 inhibitors in prostate cancers that lack the AR is unclear. In this study, we showed that BRD4, CBP, and p300 were co-expressed in AR-positive and AR-null prostate cancer. A combined inhibitor of these three proteins, NEO2734, reduced the growth of both AR-positive and AR-null organoids, as measured by changes in viability, size, and composit..
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Awarded by University of Melbourne
Funding Acknowledgements
We acknowledge the people of the Kulin Nations, on whose land these studies were carried out. We pay our respects to their Elders, past and present. We also acknowledge the members of the Prostate Cancer Research program, the patients, families, and consumers who support our research, and the members of the Melbourne Urological Research Alliance (MURAL). For expert assistance, we thank Andrew Bakshi, David Botros, Ashlee Clark, Georgia Cuffe, Jenna Kraska, Melissa Papargiris, Michelle Richards, Mahsa Rostamian Delavar, Hipacia Werneck Gomes, and Prue O'Hare. Thank you to Francis Giles for providing access to NEO2734. The prostate cancer PDX tissue microarray was provided from the Movember Global Action Plan 1 auspiced by MD Anderson Cancer Centre. This work was supported by the National Health and Medical Research Council, Australia (1138242; 1185616); Department of Health and Human Services acting through the Victorian Cancer Agency (MCRF15023, MCRF18017, MCRF17005); the US Department of Defense through the Prostate Cancer Research Program (GPR W81XWH1810349; opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense); the CASS Foundation (7139); the EJ Whitten Foundation; Movember Foundation (Global Action Plan 1); the Peter and Lyndy White Foundation; the Rotary Club of Manningham; and TissuPath Pathology. This research was supported by the CASCADE rapid autopsy program, Monash Biomedicine Discovery Institute Organoid Program, Monash University Histology Platform, Monash University Animal Research Laboratories, Peter MacCallum Centre Molecular Genomics Core, and the NeCTAR Research Cloud, a collaborative Australian research platform supported by the National Collaborative Research Infrastructure Strategy. The Victorian Centre for Functional Genomics (KJS) is funded by the Australian Cancer Research Foundation (ACRF), Phenomics Australia (PA) through funding from the Australian Government's National Collaborative Research Infrastructure Scheme (NCRIS), the Peter MacCallum Cancer Centre Foundation, and the University of Melbourne Research Collaborative Infrastructure Program (MCRIP). Open access publishing facilitated by Monash University, as part of the Wiley - Monash University agreement via the Council of Australian University Librarians.