期刊
EUROPEAN UROLOGY
卷 74, 期 5, 页码 562-572出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.eururo.2018.06.020
关键词
Abiraterone; Androgen receptor; Castration-resistant prostate cancer; Enzalutamide; Explant; Neuroendocrine prostate cancer; Organoid; Patient-derived xenograft; Prostate cancer; Ribosome
资金
- National Health and Medical Research Council of Australia [1035721, 1102752, 1052904, 1090204, 1138242, 1121057]
- Department of Health and Human Services acting through the Victorian Cancer Agency (CAPTIV Program) [13033, MCRF16007, MCRF15023]
- U.S. National Institutes of Health [R01CA174777]
- Prostate Cancer Foundation of Australia fellowship
- Prostate Cancer Foundation
- Movember-Prostate Cancer Foundation
- CASS Foundation [7139]
- MINIECO [IJCI-2014-19129]
- Peter MacCallum Cancer Foundation
- EJ Whitten Foundation
- Peter and Lyndy White Foundation
- TissuPath Pathology
- Cancer Australia [1084546]
- NATIONAL CANCER INSTITUTE [R01CA174777] Funding Source: NIH RePORTER
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. (C) 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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