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Shafi AA , Schiewer MJ , de Leeuw R , Dylgjeri E , McCue PA , Shah N , Gomella LG , Lallas CD , Trabulsi EJ , Centenera MM , Hickey TE , Butler LM , Raj G , Tilley WD , Cukierman E , Knudsen KE
Patient-derived Models Reveal Impact of the Tumor Microenvironment on Therapeutic Response
Eur Urol Oncol. 2018 Sep;1(4) :325-337
PMID: 30467556    PMCID: PMC6241309   
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Background: 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. Objective: 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. Design setting and participants: Fresh PCa tissue from patients who underwent radical prostatectomy was cultured as PDEs to examine therapeutic response. Outcome measurements and statistical analysis: The impact of genomic and chemical perturbations in PDEs was assessed using various parameters (eg, AR levels, Ki67 staining, and desmoplastic indices). Results and limitations: 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. Conclusions: 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. Patient summary: 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.
2588-9311 Shafi, Ayesha A Schiewer, Matthew J de Leeuw, Renee Dylgjeri, Emanuela McCue, Peter A Shah, Neelima Gomella, Leonard G Lallas, Costas D Trabulsi, Edouard J Centenera, Margaret M Hickey, Theresa E Butler, Lisa M Raj, Ganesh Tilley, Wayne D Cukierman, Edna Knudsen, Karen E R01 CA113451/CA/NCI NIH HHS/United States R01 CA217329/CA/NCI NIH HHS/United States R01 CA159945/CA/NCI NIH HHS/United States R01 CA182569/CA/NCI NIH HHS/United States R01 CA176401/CA/NCI NIH HHS/United States P30 CA006927/CA/NCI NIH HHS/United States P30 CA056036/CA/NCI NIH HHS/United States Journal Article Netherlands Eur Urol Oncol. 2018 Sep;1(4):325-337. doi: 10.1016/j.euo.2018.04.019. Epub 2018 Jun 6.