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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
Molecular Phenotyping of AR Signaling for Predicting Targeted Therapy in Castration Resistant Prostate Cancer
Agus Rizal A H Hamid1,2, Maria V Luna-Velez1, Aleksandra M Dudek1
1Department of Urology, Radboud University Medical Center, Nijmegen, Netherlands.
Abstract:
Castration-resistant prostate cancer (CRPC) is defined by resistance of the tumor to androgen deprivation therapy (ADT). Several molecular changes, particularly in the AR signaling cascade, have been described that may explain ADT resistance. The variety of changes may also explain why the response to novel therapies varies between patients. Testing the specific molecular changes may be a major step towards personalized treatment of CRPC patients. The aim of our study was to evaluate the molecular changes in the AR signaling cascade in CRPC patients. We have developed and validated several methods which are easy to use, and require little tissue material, for exploring AR signaling pathway changes simultaneously. We found that the AR signaling pathway is still active in the majority of our CRPC patients, due to molecular changes in AR signaling components. There was heterogeneity in the molecular changes observed, but we could classify the patients into 4 major subgroups which are: AR mutation, AR amplification, active intratumoral steroidogenesis, and combination of AR amplification and active intratumoral steroidogenesis. We suggest characterizing the AR signaling pathway in CRPC patients before beginning any new treatment, and a recent fresh tissue sample from the prostate or a metastatic site should be obtained for the purpose of this characterization.
Insights
Castration-resistant prostate cancer (CRPC) remains active due to molecular changes in the androgen receptor (AR) signaling pathway. Characterizing these AR pathway alterations is key for personalized CRPC treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Urology
Background:
- Castration-resistant prostate cancer (CRPC) develops resistance to androgen deprivation therapy (ADT).
- Molecular alterations in the androgen receptor (AR) signaling cascade are implicated in ADT resistance.
- Patient response to novel therapies for CRPC varies, suggesting underlying molecular heterogeneity.
Purpose of the Study:
- To evaluate molecular changes within the AR signaling cascade in CRPC patients.
- To establish methods for simultaneous exploration of AR signaling pathway alterations.
- To identify potential biomarkers for personalized CRPC treatment.
Main Methods:
- Development and validation of user-friendly methods requiring minimal tissue.
- Simultaneous analysis of multiple AR signaling pathway components.
- Classification of CRPC patients based on molecular profiles.
Main Results:
- The AR signaling pathway remains active in most CRPC patients studied.
- Molecular changes in AR signaling components drive pathway activity.
- Observed heterogeneity allowed classification into four subgroups: AR mutation, AR amplification, active intratumoral steroidogenesis, and combinations thereof.
Conclusions:
- The AR signaling pathway is frequently active in CRPC due to specific molecular alterations.
- CRPC patients can be subgrouped based on distinct AR pathway molecular changes.
- Characterizing the AR signaling pathway in CRPC patients prior to treatment is recommended, utilizing fresh tissue samples.
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