Dataset Information

Molecular Phenotyping of AR Signaling for Predicting Targeted Therapy in Castration Resistant Prostate Cancer.

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.

SUBMITTER: Hamid ARAH

PROVIDER: S-EPMC8417043 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Molecular Phenotyping of AR Signaling for Predicting Targeted Therapy in Castration Resistant Prostate Cancer.

Hamid Agus Rizal A H ARAH Luna-Velez Maria V MV Dudek Aleksandra M AM Jansen Cornelius F J CFJ Smit Frank F Aalders Tilly W TW Verhaegh Gerald W GW Schaafsma Ewout E Sedelaar John P M JPM Schalken Jack A JA

Frontiers in oncology 20210819

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 molecul ...[more]

PMID: 34490120

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Project description:Introduction:Prostate cancer (PCa) is the most commonly diagnosed cancer and the third leading cause of cancer-related death in males in the United States. Despite the initial efficacy of androgen deprivation therapy in prostate cancer (PCa) patients, most patients progress to castration-resistant prostate cancer. However, the mechanisms underlying the androgen-independent progression of PCa remain largely unknown. Methods:In this study, we established a PCa cell line (LNCaP-AI) by maintaining LNCaP cells under androgen-depleted conditions. To explore the cellular and molecular mechanisms of androgen-independent growth of PCa, we analyzed the gene expression patterns in androgen-independent prostate cancer (AIPC) compared with that in androgen-dependent prostate cancer (ADPC). KEGG pathway analysis revealed that Wnt signaling pathways were activated after androgen deprivation therapy (ADT). In vitro experiments showed that the inhibition of Wnt pathway reduced AIPC cell growth by inhibiting cell cycle progression and promoting apoptosis. Furthermore, WNT5A, LEF1 were identified as direct targets of AR by chromatin immunoprecipitation (ChIP) assay and public ChIP-seq datasets analysis. Results:In the present study, we found a regulatory mechanism through which crosstalk between androgen receptor (AR) and Wnt signals promoted androgen-independent conversion of PCa. The Wnt pathway was inhibited by androgen in androgen-dependent prostate cancer cells, but this blocking effect was not elicited in androgen-independent prostate cancer (AIPC) cells. Moreover, Wnt pathway genes WNT5A and LEF1 were directly downregulated by AR. In vitro experiments showed that inhibition of the Wnt pathways repressed AIPC cell growth by inhibiting cell cycle progression and promoting apoptosis. We found that WNT5A and LEF1 were downregulated in low-grade PCa but upregulated in metastatic PCa. Conclusion:In summary, we revealed that crosstalk between AR and Wnt signaling pathways promotes androgen-independent growth of PCa, which may provide novel therapeutic opportunities for castration-resistant prostate cancer.

Project description:Abstract Context Second‐generation androgen receptor inhibitors (ARIs) extend metastasis‐free survival, prolong overall survival, and delay symptoms when added to androgen deprivation therapy for the treatment of castration‐sensitive or castration‐resistant prostate cancer (CRPC). However, ARIs may adversely impact physical and cognitive function, thereby decreasing quality of life and prognosis. Objective To evaluate the evidence regarding the potential effects of ARIs on physical and cognitive function and to contextualize how drug‐related adverse effects may influence treatment decisions in CRPC. Evidence acquisition We performed a literature search using MEDLINE from January 1998 to June 2020 using terms relating to prostate cancer, androgen deprivation, and physical and cognitive function. We selected 61 publications for analysis. Evidence synthesis Treatment‐induced deterioration in physical and cognitive function may impair the independence and well‐being of patients with CRPC. Patient‐reported outcomes from clinical trials of ARIs provide quantitative evidence of their impact on these domains, which appears to vary between ARIs, reflecting the different adverse event profiles of these agents. Thus, the risk of physical or cognitive dysfunction may be managed or mitigated by appropriate selection of treatment options. Studies in patients with CRPC have assessed the cognitive effects of ARIs with validated instruments, whereas quantitative analysis of the impact on physical function has been limited. Conclusion Several validated instruments utilized for the assessment of physical and cognitive function in clinical studies have been adapted for clinical practice; however, consensus on the standardization of these assessments is required. Future clinical studies employing validated tools may generate data on the impact of ARIs and guide treatment decisions for patients with CRPC. Patient summary We review the hormonal therapies used to treat men with prostate cancer and the effects they have on physical and cognitive function. We discuss how to measure these effects and how this may assist when choosing treatment.

Dataset Information

Molecular Phenotyping of AR Signaling for Predicting Targeted Therapy in Castration Resistant Prostate Cancer.

Publications

Molecular Phenotyping of AR Signaling for Predicting Targeted Therapy in Castration Resistant Prostate Cancer.

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