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.
| Original language | English |
|---|---|
| Pages (from-to) | 562-572 |
| Number of pages | 11 |
| Journal | European Urology |
| Volume | 74 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 1 Nov 2018 |
Keywords
- Abiraterone
- Androgen receptor
- Castration-resistant prostate cancer
- Enzalutamide
- Explant
- Neuroendocrine prostate cancer
- Organoid
- Patient-derived xenograft
- Prostate cancer
- Ribosome
Cite this
}
Patient-derived Models of Abiraterone- and Enzalutamide-resistant Prostate Cancer Reveal Sensitivity to Ribosome-directed Therapy. / Lawrence, Mitchell G.; Obinata, Daisuke; Sandhu, Shahneen; Selth, Luke A.; Wong, Stephen Q.; Porter, Laura H.; Lister, Natalie; Pook, David; Pezaro, Carmel J.; Goode, David L.; Rebello, Richard J.; Clark, Ashlee K.; Papargiris, Melissa; Van Gramberg, Jenna; Hanson, Adrienne R.; Banks, Patricia; Wang, Hong; Niranjan, Birunthi; Keerthikumar, Shivakumar; Hedwards, Shelley; Huglo, Alisee; Yang, Rendong; Henzler, Christine; Li, Yingming; Lopez-Campos, Fernando; Castro, Elena; Toivanen, Roxanne; Azad, Arun; Bolton, Damien; Goad, Jeremy; Grummet, Jeremy; Harewood, Laurence; Kourambas, John; Lawrentschuk, Nathan; Moon, Daniel; Murphy, Declan G.; Sengupta, Shomik; Snow, Ross; Thorne, Heather; Mitchell, Catherine; Pedersen, John; Clouston, David; Norden, Sam; Ryan, Andrew; Dehm, Scott M.; Tilley, Wayne D.; Pearson, Richard B.; Hannan, Ross D.; Frydenberg, Mark; Furic, Luc; Taylor, Renea A.; Risbridger, Gail P.
In: European Urology, Vol. 74, No. 5, 01.11.2018, p. 562-572.Research output: Contribution to journal › Article › Research › peer-review
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 - 2018/11/1
Y1 - 2018/11/1
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.
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.
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
U2 - 10.1016/j.eururo.2018.06.020
DO - 10.1016/j.eururo.2018.06.020
M3 - Article
C2 - 30049486
VL - 74
SP - 562
EP - 572
JO - European Urology
JF - European Urology
SN - 0302-2838
IS - 5
ER -