Patient-derived Models of Abiraterone- and Enzalutamide-resistant Prostate Cancer Reveal Sensitivity to Ribosome-directed Therapy

Mitchell G. Lawrence; Daisuke Obinata; Shahneen Sandhu; Luke A. Selth; Stephen Q. Wong; Laura H. Porter; Natalie Lister; David Pook; Carmel J. Pezaro; David L. Goode; Richard J. Rebello; Ashlee K. Clark; Melissa Papargiris; Jenna Van Gramberg; Adrienne R. Hanson; Patricia Banks; Hong Wang; Birunthi Niranjan; Shivakumar Keerthikumar; Shelley Hedwards; Alisee Huglo; Rendong Yang; Christine Henzler; Yingming Li; Fernando Lopez-Campos; Elena Castro; Roxanne Toivanen; Arun Azad; Damien Bolton; Jeremy Goad; Jeremy Grummet; Laurence Harewood; John Kourambas; Nathan Lawrentschuk; Daniel Moon; Declan G. Murphy; Shomik Sengupta; Ross Snow; Heather Thorne; Catherine Mitchell; John Pedersen; David Clouston; Sam Norden; Andrew Ryan; Scott M. Dehm; Wayne D. Tilley; Richard B. Pearson; Ross D. Hannan; Mark Frydenberg; Luc Furic; Renea A. Taylor; Gail P. Risbridger

doi:10.1016/j.eururo.2018.06.020

Patient-derived Models of Abiraterone- and Enzalutamide-resistant Prostate Cancer Reveal Sensitivity to Ribosome-directed Therapy

Mitchell G. Lawrence, Daisuke Obinata, Shahneen Sandhu, Luke A. Selth, Stephen Q. Wong, Laura H. Porter, Natalie Lister, David Pook, Carmel J. Pezaro, David L. Goode, Richard J. Rebello, Ashlee K. Clark, Melissa Papargiris, Jenna Van Gramberg, Adrienne R. Hanson, Patricia Banks, Hong Wang, Birunthi Niranjan, Shivakumar Keerthikumar, Shelley HedwardsAlisee Huglo, Rendong Yang, Christine Henzler, Yingming Li, Fernando Lopez-Campos, Elena Castro, Roxanne Toivanen, Arun Azad, Damien Bolton, Jeremy Goad, Jeremy Grummet, Laurence Harewood, John Kourambas, Nathan Lawrentschuk, Daniel Moon, Declan G. Murphy, Shomik Sengupta, Ross Snow, Heather Thorne, Catherine Mitchell, John Pedersen, David Clouston, Sam Norden, Andrew Ryan, Scott M. Dehm, Wayne D. Tilley, Richard B. Pearson, Ross D. Hannan, Mark Frydenberg, Luc Furic, Renea A. Taylor, Gail P. Risbridger^*

^*Corresponding author for this work

Urology

Research output: Contribution to journal › Article › peer-review

83 Scopus citations

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. 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.

Original language	English (US)
Pages (from-to)	562-572
Number of pages	11
Journal	European urology
Volume	74
Issue number	5
DOIs	https://doi.org/10.1016/j.eururo.2018.06.020
State	Published - Nov 2018

Funding

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.

Keywords

Abiraterone
Androgen receptor
Castration-resistant prostate cancer
Enzalutamide
Explant
Neuroendocrine prostate cancer
Organoid
Patient-derived xenograft
Prostate cancer
Ribosome

ASJC Scopus subject areas

Urology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.eururo.2018.06.020

Cite this

Lawrence, M. G., Obinata, D., Sandhu, S., Selth, L. A., Wong, S. Q., Porter, L. H., Lister, N., Pook, D., Pezaro, C. J., Goode, D. L., Rebello, R. J., Clark, A. K., Papargiris, M., Van Gramberg, J., Hanson, A. R., Banks, P., Wang, H., Niranjan, B., Keerthikumar, S., ... Risbridger, G. P. (2018). Patient-derived Models of Abiraterone- and Enzalutamide-resistant Prostate Cancer Reveal Sensitivity to Ribosome-directed Therapy. European urology, 74(5), 562-572. https://doi.org/10.1016/j.eururo.2018.06.020

@article{3004a31473e04240ba77e25d75433844,

title = "Patient-derived Models of Abiraterone- and Enzalutamide-resistant Prostate Cancer Reveal Sensitivity to Ribosome-directed Therapy",

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. 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.",

keywords = "Abiraterone, Androgen receptor, Castration-resistant prostate cancer, Enzalutamide, Explant, Neuroendocrine prostate cancer, Organoid, Patient-derived xenograft, Prostate cancer, Ribosome",

author = "Lawrence, {Mitchell G.} and Daisuke Obinata and Shahneen Sandhu and Selth, {Luke A.} and Wong, {Stephen Q.} and Porter, {Laura H.} and Natalie Lister and David Pook and Pezaro, {Carmel J.} and Goode, {David L.} and Rebello, {Richard J.} and Clark, {Ashlee K.} and Melissa Papargiris and {Van Gramberg}, Jenna and Hanson, {Adrienne R.} and Patricia Banks and Hong Wang and Birunthi Niranjan and Shivakumar Keerthikumar and Shelley Hedwards and Alisee Huglo and Rendong Yang and Christine Henzler and Yingming Li and Fernando Lopez-Campos and Elena Castro and Roxanne Toivanen and Arun Azad and Damien Bolton and Jeremy Goad and Jeremy Grummet and Laurence Harewood and John Kourambas and Nathan Lawrentschuk and Daniel Moon and Murphy, {Declan G.} and Shomik Sengupta and Ross Snow and Heather Thorne and Catherine Mitchell and John Pedersen and David Clouston and Sam Norden and Andrew Ryan and Dehm, {Scott M.} and Tilley, {Wayne D.} and Pearson, {Richard B.} and Hannan, {Ross D.} and Mark Frydenberg and Luc Furic and Taylor, {Renea A.} and Risbridger, {Gail P.}",

note = "Publisher Copyright: {\textcopyright} 2018 European Association of Urology",

year = "2018",

month = nov,

doi = "10.1016/j.eururo.2018.06.020",

language = "English (US)",

volume = "74",

pages = "562--572",

journal = "European urology",

issn = "0302-2838",

publisher = "Elsevier",

number = "5",

}

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 & Risbridger, GP 2018, 'Patient-derived Models of Abiraterone- and Enzalutamide-resistant Prostate Cancer Reveal Sensitivity to Ribosome-directed Therapy', European urology, vol. 74, no. 5, pp. 562-572. https://doi.org/10.1016/j.eururo.2018.06.020

TY - JOUR

T1 - Patient-derived Models of Abiraterone- and Enzalutamide-resistant Prostate Cancer Reveal Sensitivity to Ribosome-directed Therapy

AU - Lawrence, Mitchell G.

AU - Obinata, Daisuke

AU - Sandhu, Shahneen

AU - Selth, Luke A.

AU - Wong, Stephen Q.

AU - Porter, Laura H.

AU - Lister, Natalie

AU - Pook, David

AU - Pezaro, Carmel J.

AU - Goode, David L.

AU - Rebello, Richard J.

AU - Clark, Ashlee K.

AU - Papargiris, Melissa

AU - Van Gramberg, Jenna

AU - Hanson, Adrienne R.

AU - Banks, Patricia

AU - Wang, Hong

AU - Niranjan, Birunthi

AU - Keerthikumar, Shivakumar

AU - Hedwards, Shelley

AU - Huglo, Alisee

AU - Yang, Rendong

AU - Henzler, Christine

AU - Li, Yingming

AU - Lopez-Campos, Fernando

AU - Castro, Elena

AU - Toivanen, Roxanne

AU - Azad, Arun

AU - Bolton, Damien

AU - Goad, Jeremy

AU - Grummet, Jeremy

AU - Harewood, Laurence

AU - Kourambas, John

AU - Lawrentschuk, Nathan

AU - Moon, Daniel

AU - Murphy, Declan G.

AU - Sengupta, Shomik

AU - Snow, Ross

AU - Thorne, Heather

AU - Mitchell, Catherine

AU - Pedersen, John

AU - Clouston, David

AU - Norden, Sam

AU - Ryan, Andrew

AU - Dehm, Scott M.

AU - Tilley, Wayne D.

AU - Pearson, Richard B.

AU - Hannan, Ross D.

AU - Frydenberg, Mark

AU - Furic, Luc

AU - Taylor, Renea A.

AU - Risbridger, Gail P.

PY - 2018/11

Y1 - 2018/11

N2 - 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.

AB - 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.

KW - Abiraterone

KW - Androgen receptor

KW - Castration-resistant prostate cancer

KW - Enzalutamide

KW - Explant

KW - Neuroendocrine prostate cancer

KW - Organoid

KW - Patient-derived xenograft

KW - Prostate cancer

KW - Ribosome

UR - http://www.scopus.com/inward/record.url?scp=85054384999&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85054384999&partnerID=8YFLogxK

U2 - 10.1016/j.eururo.2018.06.020

DO - 10.1016/j.eururo.2018.06.020

M3 - Article

C2 - 30049486

AN - SCOPUS:85054384999

SN - 0302-2838

VL - 74

SP - 562

EP - 572

JO - European urology

JF - European urology

IS - 5

ER -

Patient-derived Models of Abiraterone- and Enzalutamide-resistant Prostate Cancer Reveal Sensitivity to Ribosome-directed Therapy

Abstract

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UN SDGs

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