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https://hdl.handle.net/2440/117372
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Type: | Journal article |
Title: | Patient-derived models of abiraterone- and enzalutamide-resistant prostate cancer reveal sensitivity to ribosome-directed therapy |
Author: | Lawrence, M. Obinata, D. Sandhu, S. Selth, L. Wong, S. Porter, L. Lister, N. Pook, D. Pezaro, C. Goode, D. Rebello, R. Clark, A. Papargiris, M. Van Gramberg, J. Hanson, A. Banks, P. Wang, H. Niranjan, B. Keerthikumar, S. Hedwards, S. et al. |
Citation: | European Urology, 2018; 74(5):562-572 |
Publisher: | Elsevier |
Issue Date: | 2018 |
ISSN: | 0302-2838 1873-7560 |
Statement of Responsibility: | Mitchell G.Lawrence, Daisuke Obinata, Shahneen Sandhu, Luke A.Selth, Stephen Q.Wong ... Wayne D.Tilley ... et al. |
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 |
Rights: | © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved. |
DOI: | 10.1016/j.eururo.2018.06.020 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1035721 http://purl.org/au-research/grants/nhmrc/1102752 http://purl.org/au-research/grants/nhmrc/1052904 http://purl.org/au-research/grants/nhmrc/1090204 http://purl.org/au-research/grants/nhmrc/1138242 http://purl.org/au-research/grants/nhmrc/1121057 |
Published version: | http://dx.doi.org/10.1016/j.eururo.2018.06.020 |
Appears in Collections: | Aurora harvest 8 Medicine publications |
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