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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
Statement of
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
Neuroendocrine prostate cancer
Patient-derived xenograft
Prostate cancer
Rights: © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
DOI: 10.1016/j.eururo.2018.06.020
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