Projects per year
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 |
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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
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Systems analyses of prostate cancer organoid cultures for precision medicine
Toivanen, R.
National Health and Medical Research Council (NHMRC) (Australia)
30/06/15 → 31/08/17
Project: Research
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Dual Targeting of the Androgen Receptor for Effective and Durable Control of Lethal Prostate Cancer
Tilley, W. D., Risbridger, G., Raj, G. V., Selth, L., Taylor, R. & Joshua, A. M.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/17 → 31/12/20
Project: Research
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A novel strategy for targeting castrate-resistant prostate cancer
Risbridger, G., Tilley, W. D., Furic, L., Sandhu, S. K., Azad, A., Selth, L. & Lawrence, M.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/18 → 31/12/21
Project: Research