1. Patient-derived Models of Abiraterone- and Enzalutamide-resistant Prostate Cancer Reveal Sensitivity to Ribosome-directed Therapy.
- Author
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Lawrence MG, Obinata D, Sandhu S, Selth LA, Wong SQ, Porter LH, Lister N, Pook D, Pezaro CJ, Goode DL, Rebello RJ, Clark AK, Papargiris M, Van Gramberg J, Hanson AR, Banks P, Wang H, Niranjan B, Keerthikumar S, Hedwards S, Huglo A, Yang R, Henzler C, Li Y, Lopez-Campos F, Castro E, Toivanen R, Azad A, Bolton D, Goad J, Grummet J, Harewood L, Kourambas J, Lawrentschuk N, Moon D, Murphy DG, Sengupta S, Snow R, Thorne H, Mitchell C, Pedersen J, Clouston D, Norden S, Ryan A, Dehm SM, Tilley WD, Pearson RB, Hannan RD, Frydenberg M, Furic L, Taylor RA, and Risbridger GP
- 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
- 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., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)
- Published
- 2018
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