Platinum Priority ā Prostate CancerEditorial by Simon J. Crabb on pp. 573ā574 of this issuePatient-derived Models of Abiraterone- and Enzalutamide-resistant Prostate Cancer Reveal Sensitivity to Ribosome-directed Therapy
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. 1AāC), 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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2022, Cancer LettersCitation Excerpt :Ribosome biogenesis has recently been viewed as a promising drug target in cancer therapy because of its increase in cancer cells and ability to sustain unrestricted growth [89]. Lawrence et al. tested the combination of RNA polymerase I inhibitor CX-5461 and pan-PIM kinase inhibitor CX-6258 in PDX-305 to examine the effect of ribosome-targeted drugs on NEPC tumors and observed that the combination could significantly reduce PDX-305 tumor growth [52]. Based on the finding that NEPC exhibits a higher degree of hypoxia, regulated by the ONECUT2-SMAD3 axis, Guo et al. assessed the efficacy of the hypoxia-directed therapy TH-302 on LTL545 and demonstrated that TH-302 treatment reduced tumor hypoxia in the tumors and significantly suppressed tumor growth [75].
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These authors contributed equally.