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Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
Quantitative characterization of androgen receptor protein expression and cellular localization in circulating tumor
Edwin E Reyes1,2, David J VanderWeele3, Masis Isikbay4
1Department of Surgery, University of Chicago, Chicago, IL, USA. ereyes18@uchicago.edu.
Background:
Many current therapies for metastatic castration-resistant prostate cancer (mCRPC) are aimed at AR signaling; however, resistance to these therapies is inevitable. To personalize CRPC therapy in an individual with clinical progression despite maximal AR signaling blockade, it is important to characterize the status of AR activity within their cancer. Biopsies of bone metastases are invasive and frequently fail to yield sufficient tissue for further study. Evaluation of circulating tumor cells (CTCs) offers an alternative, minimally invasive mechanism to characterize and study late-stage disease. The goal of this study was to evaluate the utility of CTC interrogation with respect to the AR as a potential novel therapeutic biomarker in patients with mCRPC.
Methods:
Fifteen mL of whole blood was collected from patients with progressive, metastatic mCRPC, the mononuclear cell portion was isolated, and fluorescence-activated cell sorting (FACS) was used to isolate and evaluate CTCs. A novel protocol was optimized to use ImageStreamX to quantitatively analyze AR expression and subcellular localization within CTCs. Co-expression of AR and the proliferation marker Ki67 was also determined using ImageStreamX.
Results:
We found inter-patient and intra-patient heterogeneity in expression and localization of AR. Increased AR expression and nuclear localization are associated with elevated co-expression of Ki-67, consistent with the continued role for AR in castration-resistant disease. Despite intra-patient heterogeneity, CTCs from patients with prior exposure to abiraterone had increased AR expression compared to CTCs from patients who were abiraterone-naïve.
Conclusions:
As our toolbox for targeting AR function expands, our ability to evaluate AR expression and function within tumor samples from patients with late-stage disease will likely be a critical component of the personalized management of advanced prostate cancer. AR expression and nuclear localization varies within patients and between patients; however it remains associated with markers of proliferation. This supports a molecularly diverse AR-centric pathobiology imparting castration-resistance.
Insights
Analyzing circulating tumor cells (CTCs) in metastatic castration-resistant prostate cancer (mCRPC) reveals varied androgen receptor (AR) expression. This heterogeneity is linked to proliferation markers and treatment history, suggesting AR
Area of Science:
- Oncology
- Urology
- Molecular Biology
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) therapies target androgen receptor (AR) signaling, but resistance is common.
- Personalized therapy requires understanding AR activity in advanced disease.
- Circulating tumor cells (CTCs) offer a minimally invasive method to study late-stage mCRPC.
Purpose of the Study:
- To assess the utility of CTCs for evaluating AR status in mCRPC patients.
- To explore AR expression and localization as potential biomarkers for personalized mCRPC treatment.
Main Methods:
- Collected blood from mCRPC patients and isolated CTCs using fluorescence-activated cell sorting (FACS).
- Utilized ImageStreamX to quantitatively analyze AR expression and subcellular localization in CTCs.
- Determined co-expression of AR and the proliferation marker Ki67 in CTCs.
Main Results:
- Observed significant inter-patient and intra-patient heterogeneity in AR expression and localization.
- Found increased AR expression and nuclear localization correlated with elevated Ki-67 co-expression.
- CTCs from abiraterone-treated patients showed higher AR expression than treatment-naïve patients.
Conclusions:
- AR expression and localization in CTCs vary significantly but remain linked to proliferation markers.
- CTC analysis provides a valuable tool for understanding AR-centric pathobiology in castration-resistant prostate cancer.
- This approach supports personalized management strategies for advanced prostate cancer by assessing AR function.
