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Patient-derived Models of Abiraterone- and Enzalutamide-resistant Prostate Cancer Reveal Sensitivity to Ribosome-directed Therapy.
- Source :
-
European urology [Eur Urol] 2018 Nov; Vol. 74 (5), pp. 562-572. Date of Electronic Publication: 2018 Jul 23. - Publication Year :
- 2018
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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.<br />Objective: To discover therapeutic strategies by exploiting patient-derived models that exemplify the heterogeneity of CRPC.<br />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.<br />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).<br />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.<br />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.<br />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.<br />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.<br /> (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Benzamides
Humans
Male
Mice, Inbred NOD
Mice, SCID
Molecular Targeted Therapy
Nitriles
Phenylthiohydantoin pharmacology
Prostatic Neoplasms, Castration-Resistant enzymology
Prostatic Neoplasms, Castration-Resistant genetics
Prostatic Neoplasms, Castration-Resistant pathology
Proto-Oncogene Proteins c-pim-1 antagonists & inhibitors
Proto-Oncogene Proteins c-pim-1 metabolism
RNA Polymerase I antagonists & inhibitors
RNA Polymerase I genetics
RNA Polymerase I metabolism
Ribosomes enzymology
Ribosomes genetics
Time Factors
Tumor Burden drug effects
Xenograft Model Antitumor Assays
Androstenes pharmacology
Antineoplastic Agents pharmacology
Antineoplastic Combined Chemotherapy Protocols pharmacology
Azepines pharmacology
Benzothiazoles pharmacology
Drug Resistance, Neoplasm
Indoles pharmacology
Naphthyridines pharmacology
Phenylthiohydantoin analogs & derivatives
Prostatic Neoplasms, Castration-Resistant drug therapy
Ribosomes drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1873-7560
- Volume :
- 74
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- European urology
- Publication Type :
- Academic Journal
- Accession number :
- 30049486
- Full Text :
- https://doi.org/10.1016/j.eururo.2018.06.020