Androgen deprivation therapy is a first-line treatment for disseminated prostate cancer (PCa). However, virtually all tumors become resistant and recur as castration-resistant PCa, which has no durable cure. One major hurdle in the development of more effective therapies is the lack of preclinical models that adequately recapitulate the heterogeneity of PCa, significantly hindering the ability to accurately predict therapeutic response.
To leverage the ex vivo culture method termed patient-derived explant (PDE) to examine the impact of PCa therapeutics on a patient-by-patient basis.
Fresh PCa tissue from patients who underwent radical prostatectomy was cultured as PDEs to examine therapeutic response.
The impact of genomic and chemical perturbations in PDEs was assessed using various parameters (eg, AR levels, Ki67 staining, and desmoplastic indices).
PDE maintained the integrity of the native tumor microenvironment (TME), tumor tissue morphology, viability, and endogenous hormone signaling. Tumor cells in this model system exhibited de novo proliferative capacity. Examination of the native TME in the PDE revealed a first-in-field insight into patient-specific desmoplastic stromal indices and predicted responsiveness to AR-directed therapeutics.
The PDE model allows for a comprehensive evaluation of individual tumors in their native TME to ultimately develop more effective therapeutic regimens tailored to individuals. Discernment of novel stromal markers may provide a basis for applying precision medicine in treating advanced PCa, which would have a transformative effect on patient outcomes.
In this study, an innovative model system was used to more effectively mimic human disease. The patient-derived explant (PDE) system can be used to predict therapeutic response and identify novel targets in advanced disease. Thus, the PDE will be an asset for the development of novel metrics for the implementation of precision medicine in prostate cancer.The patient-derived explant (PDE) model allows for a comprehensive evaluation of individual human tumors in their native tumor microenvironment (TME). TME analysis revealed first-in-field insight into predicted tumor responsiveness to AR-directed therapeutics through evaluation of patient-specific desmoplastic stromal indices.
European urology oncology. 2018 Jun 06 [Epub]
Ayesha A Shafi, Matthew J Schiewer, Renée de Leeuw, Emanuela Dylgjeri, Peter A McCue, Neelima Shah, Leonard G Gomella, Costas D Lallas, Edouard J Trabulsi, Margaret M Centenera, Theresa E Hickey, Lisa M Butler, Ganesh Raj, Wayne D Tilley, Edna Cukierman, Karen E Knudsen
Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA., Cancer Biology, Fox Chase Cancer Center, Temple Health, Philadelphia, PA, USA., Dame Roma Mitchell Cancer Research Laboratories, Adelaide Prostate Cancer Research Centre and Freemason's Foundation Centre for Men's Health, School of Medicine, University of Adelaide, Adelaide, Australia., University of Texas Southwestern Medical Center, Dallas, TX, USA.