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Eur Urol. 2018 Nov;74(5):562-572. doi: 10.1016/j.eururo.2018.06.020. Epub 2018 Jul 23.

Patient-derived Models of Abiraterone- and Enzalutamide-resistant Prostate Cancer Reveal Sensitivity to Ribosome-directed Therapy.

Author information

1
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.
2
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.
3
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.
4
Dame Roma Mitchell Cancer Research Laboratories and Freemasons Foundation Centre for Men's Health, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.
5
Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Molecular Biomarkers and Translational Genomics Lab, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
6
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; Medical Oncology, Monash Health, Clayton, VIC, Australia.
7
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; Eastern Health and Monash University Eastern Health Clinical School, Box Hill, VIC, Australia.
8
Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia; Computational Cancer Biology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
9
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.
10
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; Melbourne Urological Research Alliance (MURAL), Melbourne, VIC, Australia; Australian Prostate Cancer Bioresource, VIC Node, Monash University, Clayton, VIC, Australia.
11
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; Australian Prostate Cancer Bioresource, VIC Node, Monash University, Clayton, VIC, Australia.
12
Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
13
Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, USA.
14
Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
15
Spanish National Cancer Research Centre, Madrid, Spain.
16
Medical Oncology, Monash Health, Clayton, VIC, Australia; Department of Medicine, School of Clinical Sciences, Monash University, Clayton, VIC, Australia.
17
Department of Urology, Austin Hospital, The University of Melbourne, Melbourne Heidelberg, VIC, Australia; Department of Surgery, The University of Melbourne, Parkville, VIC, Australia.
18
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia; Division of Cancer Surgery, Peter MacCallum Cancer Centre, The University of Melbourne, Melbourne, VIC, Australia; Epworth Healthcare, Melbourne, VIC, Australia.
19
Epworth Healthcare, Melbourne, VIC, Australia; Department of Surgery, Central Clinical School, Monash University, Clayton, VIC, Australia; Australian Urology Associates, Melbourne, VIC, Australia.
20
Department of Surgery, The University of Melbourne, Parkville, VIC, Australia; Epworth Healthcare, Melbourne, VIC, Australia.
21
Department of Medicine, Monash Health, Casey Hospital, Berwick, VIC, Australia.
22
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, VIC, Australia.
23
Division of Cancer Surgery, Peter MacCallum Cancer Centre, The University of Melbourne, Melbourne, VIC, Australia; Epworth Healthcare, Melbourne, VIC, Australia; Australian Urology Associates, Melbourne, VIC, Australia; Central Clinical School, Monash University, Clayton, VIC, Australia; The Epworth Prostate Centre, Epworth Hospital, Richmond, VIC, Australia.
24
Eastern Health and Monash University Eastern Health Clinical School, Box Hill, VIC, Australia; Department of Urology, Austin Hospital, The University of Melbourne, Melbourne Heidelberg, VIC, Australia; Epworth Healthcare, Melbourne, VIC, Australia; Department of Surgery, Austin Health, The University of Melbourne, Heidelberg, VIC, Australia; Epworth Freemasons, Epworth Health, East Melbourne, VIC, Australia.
25
Australian Urology Associates, Melbourne, VIC, Australia.
26
Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia; kConFab, Research Department, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
27
Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
28
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; TissuPath, Mount Waverley, VIC, Australia.
29
TissuPath, Mount Waverley, VIC, Australia.
30
Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Departments of Laboratory Medicine and Pathology and Urology, University of Minnesota, Minneapolis, MN, USA.
31
Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia; 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.
32
Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 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.
33
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; Epworth Healthcare, Melbourne, VIC, Australia; Australian Urology Associates, Melbourne, VIC, Australia; Department of Surgery, Monash University, Clayton, VIC, Australia.
34
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; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia.
35
Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Melbourne Urological Research Alliance (MURAL), Melbourne, VIC, Australia; Monash Partners Comprehensive Cancer Consortium, Monash Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Group, Department of Physiology, Monash University, Clayton, VIC, Australia.
36
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. Electronic address: gail.risbridger@monash.edu.

Abstract

BACKGROUND:

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.

OBJECTIVE:

To discover therapeutic strategies by exploiting patient-derived models that exemplify the heterogeneity of CRPC.

DESIGN, SETTING, AND PARTICIPANTS:

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.

INTERVENTION:

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).

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:

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.

RESULTS AND LIMITATIONS:

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.

CONCLUSIONS:

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.

PATIENT SUMMARY:

Diverse types of therapy-resistant prostate cancers are sensitive to a new combination of drugs that inhibit protein synthesis pathways in cancer cells.

KEYWORDS:

Abiraterone; Androgen receptor; Castration-resistant prostate cancer; Enzalutamide; Explant; Neuroendocrine prostate cancer; Organoid; Patient-derived xenograft; Prostate cancer; Ribosome

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