New patient-derived models of castrate-sensitive and castrate-resistant prostate cancer.

Authors

null

Mitchell Lawrence

Prostate Cancer Research Group, Victoria, Australia

Mitchell Lawrence , David Clouston , Mark Frydenberg , Declan G. Murphy , Carmel Jo Pezaro , David William Pook , Heather Thorne , Shahneen Kaur Sandhu , Roxanne Toivanen , Renea Taylor , Gail Risbridger

Organizations

Prostate Cancer Research Group, Victoria, Australia, TissuPath, Melbourne, Australia, Monash University, Clayton, Australia, Peter MacCallum Cancer Centre, Melbourne, Australia, Eastern Health Clinical School, Monash University, Melbourne, Australia, Department of Medical Oncology, Monash Health, Melbourne, VIC, Australia, Peter MacCallum Cancer Centre, The University of Melbourne, Melbourne, Australia, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia, Prostate Cancer Research Group, Monash University, Victoria, Australia

Research Funding

Other Government Agency
Australian National Health and Medical Research Council., Victorian Cancer Agency, EJ Whitten Foundation, Movember, Endocrine Society of Australia, CASS Foundation.

Background: There are fewer preclinical models of prostate cancer compared to other common tumours. New models that represent the diverse features of castrate-sensitive and castration-resistant prostate cancer (CRPC) are required for thorough preclinical testing of novel treatments. Therefore, the goal of the Melbourne Urological Research Alliance (MURAL) is to develop patient-derived xenografts (PDXs) spanning the clinical trajectory of prostate cancer. Methods: We grafted >200 surgery, biopsy or rapid autopsy samples into testosterone-supplemented or castrated male NSG mice. Actively growing tumours were serially transplanted or grown as explants or organoids. PDXs were analysed using RNAseq, targeted genomic sequencing and histopathology review. Results: We previously reported 4 serially transplantable PDXs (Lawrence, et al., 2018, European Urology). Now we have established ~30 additional models spanning treatment naïve primary disease to CRPC. PDXs of CRPC were often from soft tissue metastases of patients who had failed docetaxel, cabazitaxel, enzalutamide, abiraterone and other contemporary treatments. Accordingly, they had diverse mechanisms of resistance, including AR mutations, genomic structural rearrangements, gene amplifications and expression of AR variants. In addition, several PDXs had AR-null phenotypes, including small cell prostate cancer. All PDXs closely reflected the genomic, transcriptomic and histopathological characteristics of the original patient tumours. As renewable sources of tissue, the PDXs could also be grown as ex vivo slice cultures and in vitro organoids, providing complementary models with different timescales and endpoints. Conclusions: We have developed a new collection of castrate-sensitive and castrate-resistant PDXs of prostate cancer, providing diverse tumours for preclinical testing of candidate treatments.

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Abstract Details

Meeting

2020 Genitourinary Cancers Symposium

Session Type

Poster Session

Session Title

Poster Session A: Prostate Cancer

Track

Prostate Cancer - Advanced,Prostate Cancer - Localized

Sub Track

Translational Research

Citation

J Clin Oncol 38, 2020 (suppl 6; abstr 151)

Abstract #

151

Poster Bd #

G9

Abstract Disclosures