Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/18783
Title: Patient-derived Models of Abiraterone- and Enzalutamide-resistant Prostate Cancer Reveal Sensitivity to Ribosome-directed Therapy.
Authors: Lawrence, Mitchell G;Obinata, Daisuke;Sandhu, Shahneen;Selth, Luke A;Wong, Stephen Q;Porter, Laura H;Lister, Natalie;Pook, David;Pezaro, Carmel J;Goode, David L;Rebello, Richard J;Clark, Ashlee K;Papargiris, Melissa;Van Gramberg, Jenna;Hanson, Adrienne R;Banks, Patricia;Wang, Hong;Niranjan, Birunthi;Keerthikumar, Shivakumar;Hedwards, Shelley;Huglo, Alisee;Yang, Rendong;Henzler, Christine;Li, Yingming;Lopez-Campos, Fernando;Castro, Elena;Toivanen, Roxanne;Azad, Arun;Bolton, Damien M;Goad, Jeremy;Grummet, Jeremy;Harewood, Laurence;Kourambas, John;Lawrentschuk, Nathan L;Moon, Daniel;Murphy, Declan G;Sengupta, Shomik;Snow, Ross;Thorne, Heather;Mitchell, Catherine;Pedersen, John;Clouston, David;Norden, Sam;Ryan, Andrew;Dehm, Scott M;Tilley, Wayne D;Pearson, Richard B;Hannan, Ross D;Frydenberg, Mark;Furic, Luc;Taylor, Renea A;Risbridger, Gail P
Affiliation: Monash Partners Comprehensive Cancer Consortium, Monash Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia
Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
Melbourne Urological Research Alliance (MURAL), Melbourne, VIC, Australia
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia
Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
Cancer Tissue Collection After Death (CASCADE) Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
Dame Roma Mitchell Cancer Research Laboratories and Freemasons Foundation Centre for Men's Health, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
Molecular Biomarkers and Translational Genomics Lab, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
Medical Oncology, Monash Health, Clayton, VIC, Australia
Eastern Health and Monash University Eastern Health Clinical School, Box Hill, VIC, Australia
Computational Cancer Biology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
Australian Prostate Cancer Bioresource, VIC Node, Monash University, Clayton, VIC, Australia
Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, USA
Spanish National Cancer Research Centre, Madrid, Spain
Department of Medicine, School of Clinical Sciences, Monash University, Clayton, VIC, Australia
Department of Urology, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Department of Surgery, The University of Melbourne, Parkville, VIC, Australia
Epworth Healthcare, Melbourne, VIC, Australia
Department of Surgery, Central Clinical School, Monash University, Clayton, VIC, Australia
Australian Urology Associates, Melbourne, VIC, Australia
Department of Medicine, Monash Health, Casey Hospital, Berwick, VIC, Australia
Division of Cancer Surgery, Peter MacCallum Cancer Centre, The University of Melbourne, Melbourne, VIC, Australia
Department of Surgery, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Central Clinical School, Monash University, Clayton, VIC, Australia
The Epworth Prostate Centre, Epworth Hospital, Richmond, VIC, Australia
Epworth Freemasons, Epworth Health, East Melbourne, VIC, Australia
kConFab, Research Department, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
TissuPath, Mount Waverley, VIC, Australia
Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
Departments of Laboratory Medicine and Pathology and Urology, University of Minnesota, Minneapolis, MN, USA
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, VIC, Australia
Oncogenic Signaling and Growth Control Program, Cancer Research Division, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia
ACRF Department of Cancer Biology and Therapeutics, John Curtin School of Medical Research, Australian National University, ACT, Australia
Department of Surgery, Monash University, Clayton, VIC, Australia
Issue Date: 13-Jul-2018
EDate: 2018-07-13
Citation: European urology 2018; online first: 13 July
Abstract: The intractability of castration-resistant prostate cancer (CRPC) is exacerbated by tumour heterogeneity, including diverse alterations to the androgen receptor (AR) axis and AR-independent phenotypes. The availability of additional models encompassing this heterogeneity would facilitate the identification of more effective therapies for CRPC. To discover therapeutic strategies by exploiting patient-derived models that exemplify the heterogeneity of CRPC. Four new patient-derived xenografts (PDXs) were established from independent metastases of two patients and characterised using integrative genomics. A panel of rationally selected drugs was tested using an innovative ex vivo PDX culture system. The following drugs were evaluated: AR signalling inhibitors (enzalutamide and galeterone), a PARP inhibitor (talazoparib), a chemotherapeutic (cisplatin), a CDK4/6 inhibitor (ribociclib), bromodomain and extraterminal (BET) protein inhibitors (iBET151 and JQ1), and inhibitors of ribosome biogenesis/function (RNA polymerase I inhibitor CX-5461 and pan-PIM kinase inhibitor CX-6258). Drug efficacy in ex vivo cultures of PDX tissues was evaluated using immunohistochemistry for Ki67 and cleaved caspase-3 levels. Candidate drugs were also tested for antitumour efficacy in vivo, with tumour volume being the primary endpoint. Two-tailed t tests were used to compare drug and control treatments. Integrative genomics revealed that the new PDXs exhibited heterogeneous mechanisms of resistance, including known and novel AR mutations, genomic structural rearrangements of the AR gene, and a neuroendocrine-like AR-null phenotype. Despite their heterogeneity, all models were sensitive to the combination of ribosome-targeting agents CX-5461 and CX-6258. This study demonstrates that ribosome-targeting drugs may be effective against diverse CRPC subtypes including AR-null disease, and highlights the potential of contemporary patient-derived models to prioritise treatment strategies for clinical translation. Diverse types of therapy-resistant prostate cancers are sensitive to a new combination of drugs that inhibit protein synthesis pathways in cancer cells.
URI: http://ahro.austin.org.au/austinjspui/handle/1/18783
DOI: 10.1016/j.eururo.2018.06.020
ORCID: 0000-0002-5145-6783
0000-0001-8553-5618
0000-0003-3357-1216
PubMed URL: 30049486
Type: Journal Article
Subjects: Abiraterone
Androgen receptor
Castration-resistant prostate cancer
Enzalutamide
Explant
Neuroendocrine prostate cancer
Organoid
Patient-derived xenograft
Prostate cancer
Ribosome
Appears in Collections:Journal articles

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