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. New treatments are urgently required for castration-resistant prostate cancers with diverse mechanisms of resistance. Using a suite of patient-derived models, we demonstrate the effectiveness of ribosome-targeting drugs across a spectrum of castration-resistant prostate cancer subtypes.
Bibliographical noteFunding Information:
Funding/Support and role of the sponsor : This work was supported by funding from the National Health and Medical Research Council of Australia (fellowships to M.G.L. 1035721, G.P.R. 1102752, D.L.G. 1052904, and R.T. 1090204; project grant 1121057 to W.D.T., L.A.S., G.P.R., and R.T.; project grant 1138242 to G.P.R., W.D.T., L.F., S.S., A.A., L.A.S., and M.G.L.), Cancer Australia (project grant 1084546 to L.F., R.D.H., R.B.P, S.S., and G.P.R), the Department of Health and Human Services acting through the Victorian Cancer Agency (Early Career Seed grant to M.G.L. 13033, fellowships to L.F. MCRF16007, R.A.T. MCRF15023, CAPTIV Program), U.S. National Institutes of Health (R01CA174777 to S.M.D.), Prostate Cancer Foundation of Australia fellowship to S.S. (YIA2013), the Prostate Cancer Foundation (Young Investigator Awards to L.A.S., E.C., and R.Y.), Movember-Prostate Cancer Foundation (Challenge Award to S.M.D.), the CASS Foundation (Medical Science grant to M.L. 7139), MINIECO (Juan de la Cierva’ fellowship to E.C. IJCI-2014-19129), the Peter MacCallum Cancer Foundation, the EJ Whitten Foundation, the Peter and Lyndy White Foundation, and TissuPath Pathology.
Acknowledgments: We thank the patients and families who generously supported this research by consenting to provide tissue. We thank the Melbourne Urological Research Alliance; Kathryn Alsop, Lisa Devereux and the CASCADE program; Wallace Crellin for invaluable advice; Gisela Mir Arnau, Tim Holloway, Michelle Richards, Tim Semple, Linda Teng, Scott Townley, and the Monash Histology Platform for expert technical assistance; Sree Appu, Nick Campbell, Paul Manohar, Nick Redgraves, and Li Ming Wong for patient recruitment; Stephen Plymate for providing the AR-V7 antibody; Helen Abud for assistance with organoid experiments; Lisa Butler and Margaret Centenera for assistance with explant experiments; Jason Li, Richard Lupat and Kaushalya Amarsinghe for assistance with bioinformatics; Jonathan Harris for advice on AR mutations; and the Australian Prostate Cancer BioResource for specimen collection. We also wish to thank, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, CancerAustralia, and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contribute to kConFab.
- Androgen receptor
- Castration-resistant prostate cancer
- Neuroendocrine prostate cancer
- Patient-derived xenograft
- Prostate cancer