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Patient-derived Models Reveal Impact of the Tumor Microenvironment on Therapeutic Response
Ayesha A Shafi1, Matthew J Schiewer1, Renée de Leeuw1
1Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
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.
Insights
A novel patient-derived explant (PDE) model preserves prostate cancer tumor microenvironments, enabling prediction of therapeutic response and guiding precision medicine for advanced disease.
Area of Science:
- Oncology
- Translational Medicine
- Cancer Biology
Background:
- Androgen deprivation therapy is a primary treatment for disseminated prostate cancer (PCa).
- Tumor resistance to therapy leads to castration-resistant PCa, lacking durable cures.
- Lack of adequate preclinical models hinders development of effective PCa therapies.
Purpose of the Study:
- To utilize the patient-derived explant (PDE) method for ex vivo analysis of PCa therapeutics.
- To assess therapeutic impact on a patient-by-patient basis.
- To investigate PCa heterogeneity and predict treatment response.
Main Methods:
- Fresh PCa tissue from radical prostatectomy was cultured as PDEs.
- Therapeutic responses were evaluated by assessing AR levels, Ki67 staining, and desmoplastic indices.
- Genomic and chemical perturbations were applied to PDEs to study their impact.
Main Results:
- PDEs maintained native tumor microenvironment (TME) integrity, morphology, viability, and hormone signaling.
- Tumor cells within the PDE model demonstrated de novo proliferative capacity.
- Analysis of native TME in PDEs provided insights into patient-specific desmoplastic indices and predicted AR-directed therapeutic responsiveness.
Conclusions:
- The PDE model enables comprehensive evaluation of individual tumors within their native TME.
- This model aids in developing personalized therapeutic regimens for advanced PCa.
- Identification of novel stromal markers may facilitate precision medicine applications for improved patient outcomes.
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