Objective:Small cell prostate carcinoma(SCPC)is a rare and highly malignant subtype of prostate cancer.SCPC frequently lacks androgen receptor(AR)and prostate-specific antigen(PSA)expression,and often responds poorly ...Objective:Small cell prostate carcinoma(SCPC)is a rare and highly malignant subtype of prostate cancer.SCPC frequently lacks androgen receptor(AR)and prostate-specific antigen(PSA)expression,and often responds poorly to androgen deprivation therapy(ADT).AR splice variant-7(AR-V7)is a truncated AR protein implicated in resistance to AR-targeting therapies.AR-V7 expression in castration-resistant prostate cancers has been evaluated extensively,and blood-based detection of AR-V7 has been associated with lack of response to abiraterone and enzalutamide.However,whether AR-V7 is expressed in SCPC is not known.Methods:Using validated antibodies,we performed immunohistochemistry(IHC)assay for the full-length AR(AR-FL)and(AR-V7)on post-ADT surgical SCPC specimens.Results:Seventy-five percent(9/12)of the specimens showed positive staining for the AR-FL with various intensities.Thirty-three percent(4/12)of the specimens showed positive staining for AR-V7.Among the specimens with positive AR-V7 staining,two samples displayed very weak staining,one sample showed weak-to-moderate staining,and one sample showed strong staining.All positive specimens displayed a heterogeneous pattern of AR-FL/AR-V7 staining.All specimens positive for AR-V7 were also positive for AR-FL.Conclusion:The study findings support the existence of measurable AR-FL and AR-V7 proteins in SCPC specimens.The results also have implications in detection of AR-V7 in specimens obtained through systemic sampling approaches such as circulating tumor cells.A positive AR-V7 finding by blood-based tests is not impossible in patients with SCPC who often demonstrate low PSA values.展开更多
Aberrant activation of androgen receptor(AR)signaling occurs in patients treated with AR-targeted therapies,contributing to the development of castration-resistant prostate cancer(CRPC)and therapeutic resistance.Over ...Aberrant activation of androgen receptor(AR)signaling occurs in patients treated with AR-targeted therapies,contributing to the development of castration-resistant prostate cancer(CRPC)and therapeutic resistance.Over the past decade,many AR variants(AR-Vs)have been identified in prostate cancer cell lines and clinical CRPC specimens.These AR-Vs lack the COOH-terminal ligand-binding domain(LBD),and may mediate constitutively active AR signaling acquired following AR-targeting therapies.AR splice variant-7(AR-V7),one of the most well characterized AR-Vs,can be reliably measured in tissue and liquid biopsy specimens,and blood-based detection of AR-V7 is a reliable indicator of poor outcome to relatively novel hormonal therapies(NHT)such as abiraterone and enzalutamide in men with metastatic CRPC(mCRPC).Given the important clinical implication of AR-Vs,this short review will focus on studies addressing how AR-Vs are regulated in prostate cancer.With regard to the molecular origin of AR-Vs,it is established that expression of AR-Vs is highly correlated with androgen deprivation and suppression of AR signaling.Therapeutic targeting of the AR axis may result in active transcription of the AR gene,elevated activities of certain components of the mRNA splicing machinery,as well as AR genomic alterations,all of which may explain the molecular origin of AR-Vs.Although a unified hypothesis is currently lacking,existing data suggest that elevated expression of AR-Vs,which in general occurs quite specifically in a cellular environment where the canonical AR signaling is suppressed,is driven by both genomic and epigenomic features acquired in the development of CRPC.展开更多
Prostate cancer cells demonstrate a remarkable ＂addiction＂ to androgen receptor （AR） signaling in all stages of disease progression. As such, suppression of AR signaling remains the therapeutic goal in systemic tr...Prostate cancer cells demonstrate a remarkable ＂addiction＂ to androgen receptor （AR） signaling in all stages of disease progression. As such, suppression of AR signaling remains the therapeutic goal in systemic treatment of prostate cancer. A number of molecular alterations arise in patients treated with AR-directed therapies. These molecular alterations may indicate the emergence of treatment resistance and may be targeted for the development of novel agents for prostate cancer. The presence of functional androgen receptor splice variants may represent a potential explanation for resistance to abiraterone and enzalutamide, newer AR-directed agents developed to treat metastatic castration-resistant prostate cancer （mCRPC）. In the last 8 years, many androgen receptor splice variants have been identified and characterized. Among these, androgen receptor splice variant-7 （AR-V7） has been investigated extensively. In AR-V7, the entire COOH-terminal ligand-binding domain of the canonical AR is truncated and replaced with a variant-specific peptide of 16 amino acids. Functionally, AR-V7 is capable of mediating constitutive nuclear localization and androgen receptor signaling in the absence of androgens, or in the presence of enzalutamide. In this review, we will focus on clinical translational studies involving detection/measurement of AR-V7. Methods have been developed to detect AR-V7 in clinical mCRPC specimens. AR-V7 can be reliably measured in both tissue and circulating tumor cells derived from mCRPC patients, making it possible to conduct both cross-sectional and longitudinal clinical correlative studies. Current evidence derived from studies focusing on detection of AR-V7 in mCRPC support its potential clinical utility as a treatment selection marker.展开更多
基金The work at Johns Hopkins University School of Medicine was supported by National Institutes of Health Grants(R01 CA185297 and P30 CA006973)Department of Defense Prostate Cancer Research Program Grants(W81XWH-15-2-0050)+1 种基金Johns Hopkins Prostate SPORE Grant(P50 CA058236)the Prostate Cancer Foundation.
文摘Objective:Small cell prostate carcinoma(SCPC)is a rare and highly malignant subtype of prostate cancer.SCPC frequently lacks androgen receptor(AR)and prostate-specific antigen(PSA)expression,and often responds poorly to androgen deprivation therapy(ADT).AR splice variant-7(AR-V7)is a truncated AR protein implicated in resistance to AR-targeting therapies.AR-V7 expression in castration-resistant prostate cancers has been evaluated extensively,and blood-based detection of AR-V7 has been associated with lack of response to abiraterone and enzalutamide.However,whether AR-V7 is expressed in SCPC is not known.Methods:Using validated antibodies,we performed immunohistochemistry(IHC)assay for the full-length AR(AR-FL)and(AR-V7)on post-ADT surgical SCPC specimens.Results:Seventy-five percent(9/12)of the specimens showed positive staining for the AR-FL with various intensities.Thirty-three percent(4/12)of the specimens showed positive staining for AR-V7.Among the specimens with positive AR-V7 staining,two samples displayed very weak staining,one sample showed weak-to-moderate staining,and one sample showed strong staining.All positive specimens displayed a heterogeneous pattern of AR-FL/AR-V7 staining.All specimens positive for AR-V7 were also positive for AR-FL.Conclusion:The study findings support the existence of measurable AR-FL and AR-V7 proteins in SCPC specimens.The results also have implications in detection of AR-V7 in specimens obtained through systemic sampling approaches such as circulating tumor cells.A positive AR-V7 finding by blood-based tests is not impossible in patients with SCPC who often demonstrate low PSA values.
基金supported by National Institutes of Health Grants(R01 CA185297 and P30 CA006973)Department of Defense Prostate Cancer Research Program Grants(W81XWH-15-2-0050)+1 种基金Johns Hopkins Prostate SPORE Grant(P50 CA058236)the Prostate Cancer Foundation.
文摘Aberrant activation of androgen receptor(AR)signaling occurs in patients treated with AR-targeted therapies,contributing to the development of castration-resistant prostate cancer(CRPC)and therapeutic resistance.Over the past decade,many AR variants(AR-Vs)have been identified in prostate cancer cell lines and clinical CRPC specimens.These AR-Vs lack the COOH-terminal ligand-binding domain(LBD),and may mediate constitutively active AR signaling acquired following AR-targeting therapies.AR splice variant-7(AR-V7),one of the most well characterized AR-Vs,can be reliably measured in tissue and liquid biopsy specimens,and blood-based detection of AR-V7 is a reliable indicator of poor outcome to relatively novel hormonal therapies(NHT)such as abiraterone and enzalutamide in men with metastatic CRPC(mCRPC).Given the important clinical implication of AR-Vs,this short review will focus on studies addressing how AR-Vs are regulated in prostate cancer.With regard to the molecular origin of AR-Vs,it is established that expression of AR-Vs is highly correlated with androgen deprivation and suppression of AR signaling.Therapeutic targeting of the AR axis may result in active transcription of the AR gene,elevated activities of certain components of the mRNA splicing machinery,as well as AR genomic alterations,all of which may explain the molecular origin of AR-Vs.Although a unified hypothesis is currently lacking,existing data suggest that elevated expression of AR-Vs,which in general occurs quite specifically in a cellular environment where the canonical AR signaling is suppressed,is driven by both genomic and epigenomic features acquired in the development of CRPC.
文摘Prostate cancer cells demonstrate a remarkable ＂addiction＂ to androgen receptor （AR） signaling in all stages of disease progression. As such, suppression of AR signaling remains the therapeutic goal in systemic treatment of prostate cancer. A number of molecular alterations arise in patients treated with AR-directed therapies. These molecular alterations may indicate the emergence of treatment resistance and may be targeted for the development of novel agents for prostate cancer. The presence of functional androgen receptor splice variants may represent a potential explanation for resistance to abiraterone and enzalutamide, newer AR-directed agents developed to treat metastatic castration-resistant prostate cancer （mCRPC）. In the last 8 years, many androgen receptor splice variants have been identified and characterized. Among these, androgen receptor splice variant-7 （AR-V7） has been investigated extensively. In AR-V7, the entire COOH-terminal ligand-binding domain of the canonical AR is truncated and replaced with a variant-specific peptide of 16 amino acids. Functionally, AR-V7 is capable of mediating constitutive nuclear localization and androgen receptor signaling in the absence of androgens, or in the presence of enzalutamide. In this review, we will focus on clinical translational studies involving detection/measurement of AR-V7. Methods have been developed to detect AR-V7 in clinical mCRPC specimens. AR-V7 can be reliably measured in both tissue and circulating tumor cells derived from mCRPC patients, making it possible to conduct both cross-sectional and longitudinal clinical correlative studies. Current evidence derived from studies focusing on detection of AR-V7 in mCRPC support its potential clinical utility as a treatment selection marker.
