Journal article

Androgen receptor enhancer amplification in matched patient-derived xenografts of primary and castrate-resistant prostate cancer

Laura H Porter, Andrew Bakshi, David Pook, Ashlee Clark, David Clouston, John Kourambas, David L Goode, Gail P Risbridger, Renea A Taylor, Mitchell G Lawrence

JOURNAL OF PATHOLOGY | WILEY | Published : 2021

Abstract

Amplifications of the androgen receptor (AR) occur in up to 80% of men with castration-resistant prostate cancer (CRPC). Recent studies highlighted that these amplifications not only span the AR gene but usually encompass a distal enhancer. This represents a newly recognised, non-coding mechanism of resistance to AR-directed therapies, including enzalutamide. To study disease progression before and after AR amplification, we used tumour samples from a castrate-sensitive primary tumour and castrate-resistant metastasis of the same patient. For subsequent functional and genomic studies, we established serially transplantable patient-derived xenografts (PDXs). Whole genome sequencing showed tha..

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Grants

Awarded by National Health and Medical Research Council, Australia


Awarded by Department of Health and Human Services acting through the Victorian Cancer Agency


Awarded by US Department of Defense through the Prostate Cancer Research Program


Awarded by CASS Foundation (Medical Science grant)


Funding Acknowledgements

We wish to acknowledge the people of the Kulin Nations; on whose land these studies were done. We pay our respects to their Elders, past and present. We thank the patients and families who generously supported this research by consenting to provide tissue; members of the Melbourne Urological Research Alliance (MURAL), Melissa Papargiris, and Jenna Kraska for providing PDXs; Wallace Crellin and James McPherson for invaluable advice; Melissa Bullock, William Jenkins, Shivakumar Keerthikumar, Samantha O'Dea, Michelle Richards, Linda Teng, and Hong Wang for laboratory assistance; Zenith Epigenetics for supplying ZEN-3694; and the Monash University Histology Platform, Monash University Animal Research Laboratories, Monash Biomedicine Discovery Institute Organoid Program, and Peter MacCallum Cancer Centre Molecular Genomics Core Facility for technical expertise. This work was supported by the National Health and Medical Research Council, Australia (fellowship 1102752 to GPR, project grants 1138242, 1121057, 1077799); the Department of Health and Human Services acting through the Victorian Cancer Agency (fellowships MCRF18017 to MGL, MCRF15023 to RAT, MCRF17005 to DLG, CAPTIV Program); the US Department of Defense through the Prostate Cancer Research Program (W81XWH1810349 to GPR; opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense); the CASS Foundation (Medical Science grant 7139 to MGL); Monash University Faculty of Medicine, Nursing and Health Sciences (Bridging Post-doctoral Fellowship to LHP); the Movember Foundation (Global Action Plan 1); the Peter MacCallum Cancer Foundation (DLG); the EJ Whitten Foundation; the Peter and Lyndy White Foundation; and TissuPath Pathology.