Elsevier

European Urology

Volume 74, Issue 5, November 2018, Pages 562-572
European Urology

Platinum Priority ā€“ Prostate Cancer
Editorial by Simon J. Crabb on pp. 573ā€“574 of this issue
Patient-derived Models of Abiraterone- and Enzalutamide-resistant Prostate Cancer Reveal Sensitivity to Ribosome-directed Therapy

https://doi.org/10.1016/j.eururo.2018.06.020Get rights and content

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.

Introduction

Over the last decade, new systemic treatments for advanced prostate cancer have extended patient survival, but raised new clinical challenges [1]. Metastatic castration-resistant prostate cancer (CRPC) often maintains androgen receptor (AR) signalling due to resistance mechanisms including intracrine androgen synthesis, genomic alterations to the AR gene (amplification, gain-of-function mutations, and rearrangements), expression of AR splice variants, and alterations to the expression or activity of AR cofactors [2]. Thus, second-generation AR-directed inhibitors, such as abiraterone or enzalutamide, have been effective; however, patients inevitably progress on these agents and diverse resistance phenotypes emerge. For example, tumours resistant to abiraterone and enzalutamide can transition towards aggressive AR-null/AR-independent phenotypes, including small cell and/or neuroendocrine (NE) cancer and double-negative (AR null and NE null) prostate cancer [3], [4], [5]. Importantly, substantial intra- and interpatient heterogeneity in these clinical and genomic features makes the development of novel therapeutic strategies challenging [6], [7].

In this study, we developed new patient-derived xenografts (PDXs) of contemporary CRPC from patients resistant to conventional androgen deprivation therapies, second-generation AR-directed inhibitors, and chemotherapy, with a broad spectrum of resistance mechanisms. We used these PDXs, as well as explants and organoids derived from them, to test candidate therapies. This strategy revealed the effectiveness of targeting ribosomes with the combination of an RNA polymerase I transcription inhibitor and a PIM kinase inhibitor. Together, this work identifies a promising therapeutic strategy to target a range of CRPC subtypes and also provides new patient-derived models of CRPC.

Section snippets

Patients and methods

See the Supplementary material for further details of all experiments.

Abiraterone- and enzalutamide-resistant tumours exhibit genomic diversity

To establish new preclinical models of prostate cancer, we collected 109 tumour samples from 29 patients via the Melbourne Urological Research Alliance (MURAL) platform (Supplementary Fig. 1A). This yielded 10 new serially transplantable PDXs (Supplementary Fig. 1B). We focused on four PDXs derived from rapid autopsy samples from two patients (27 and 201) with CRPC who had exhausted multiple treatments, including enzalutamide and/or abiraterone (Fig. 1Aā€“C), surmising that these aggressive

Discussion

Despite radical changes in the treatment of CRPC, including the approval of new AR-targeted therapies (abiraterone and enzalutamide), chemotherapies, immunotherapy, and bone-targeted agents, this disease remains incurable and a major cause of cancer mortality [31]. In this study, we developed new PDXs of CRPC as models to test novel therapeutics. A limitation of establishing serially transplantable PDXs of prostate cancer is the low take rate compared to other tumour types [32]. We generated 10

Conclusions

We established new PDXs of CRPC from men who failed abiraterone and/or enzalutamide and chemotherapy, including an AR-null tumour with NE features. Importantly, we showed that all these CRPC models are sensitive to dual inhibition of ribosome production and function. Since ribosome targeting agents are in clinical trials for haematological malignancies and breast cancer [38], [39], [45], [46], our findings provide a strong rationale to pursue clinical trials of these drugs in CRPC.

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