Novel anti-androgen receptor signaling agents:Understanding the mechanisms of resistance

Prostate cancer remains an intractable threat to the lives of men worldwide.Although deaths from prostate cancer(PCa)in the United States have declined in recent years,in other parts of the world Pca mortality is increasing.The introduction of 2nd generation antiandrogen receptor agents into the therapeutic armamentarium for metastatic castrationresistant prostate cancer(mCRPC)has resulted in modestly increased survival advantages as demonstrated by initial clinical trials.However,analysis of the molecular pathways affected by these agents may lead to new insight into mechanisms of resistance that drive mCRPC,including proliferation and survival signaling pathways that are derepressed by maximum repression of androgen signaling.Combination therapies that involve anti-AR signaling agents together with agents that target these pathways establish a paradigm for the development of more effective treatment of mCRPC.In this review,we briefly summarize the current clinical trial literature with regard to novel anti-AR signaling agents such as abiraterone acetate and enzalutamide.We discuss observational data that point to mechanisms of resistance that emerged from these studies.We further present and discuss recent experimental studies that address the mechanisms of resistance to these treatments.Finally,we discuss novel and rational therapeutic approaches,including combination therapy,for patients with mCRPC.

Cytopathic effects and local immune responses in repeated neoadjuvant HSV-tk+ ganciclovir gene therapy for prostate cancer

Objective:Cytopathic effects and local immune response were analyzed histologically in prostatic cancer(PCa)with in situ herpes simplex virus-thymidine kinase(HSV-tk)/ganciclovir(GCV)gene therapy(GT).Methods:Four high-risk PCa patients who received HSV-tk/GCV GT were investigated.After two cycles of intraprostatic injection of HSV-tk and administration of GCV,radical prostatectomy was performed.Formalin-fixed,paraffin-embedded sections were evaluated using immunohistochemistry.PCa with hormone therapy(HT,n=3)or without neoadjuvant therapy(NT,n=4)that were equivalent in terms of risk were also examined as reference.Immunoreactively-positive cells were counted in at least three areas in cancer tissue.Labeling indices(LI)were calculated as percentage values.Results:ssDNA LI in GT increased,indicating apoptosis,as well as tumor-infiltrating lymphocytes and CD68-positive macrophages,compared with their biopsies.GT cases showed significantly higher numbers of single-stranded DNA(ssDNA)LI,CD4/CD8-positive T cells and CD68-positive macrophages including M1/M2 macrophages than HT or NT cases.However,there was no significant difference in CD20-positive B cells among the types of case.There were strong correlations between CD8+T cells and CD68+macrophages(ρ=0.656,p<0.0001)as well as CD4+T cells and CD20+B cells(ρ=0.644,p<0.0001)in PCa with GT.Conclusions:Enhanced cytopathic effect and local immune response might be indicated in PCa patients with HSV-tk/GCV gene therapy.

DNA Damage Response Inhibitor and Anti-PD-L1 Therapy for Prostate Cancer: Development of Predictive Biomarkers

1.Introduction Although androgen receptor biosynthesis and signaling inhibi-tors have significantly improved outcomes in patients with castra-tion-resistant prostate cancer(CRPC),there is still a dearth of effective treatment options for men with advanced prostate cancer.

Follistatin-like protein 1 plays a tumor suppressor role in clear-cell renal cell carcinoma

Background:We previously showed that the expression of follistatin-like protein 1(FSTL1)was significantly down-regulated in metastatic clear-cell renal cell carcinoma(ccRCC).In this study,we aimed to characterize the role of FSTL1 in the development of ccRCC.Methods:The effects of FSTL1 on cell activity and cell cycle were investigated in ccRCC cell lines with altered FSTL1 expression.Gene expression microarray assays were performed to identify the major signaling pathways affected by FSTL1 knockdown.The expression of FSTL1 in ccRCC and its effect on postoperative prognosis were estimated in a cohort with 89 patients.Results:FSTL1 knockdown promoted anchorage-independent growth,migration,invasion,and cell cycle of ccRCC cell lines,whereas FSTL1 overexpression attenuated cell migration.FSTL1 knockdown up-regulated nuclear factor-κB(NF-κB)and hypoxia-inducible factor(HIF)signaling pathways,increased epithelial-to-mesenchymal transition,up-regulated interleukin-6 expression,and promoted tumor necrosis factor-α-induced degradation of NF-κB inhibitor(IκBα)in ccRCC cell lines.FSTL1 immunostaining was selectively positive in epithelial cytoplasm in the loop of Henle,and positive rate of FSTL1 was significantly lower in ccRCC tissues than in adjacent renal tissues(P<0.001).The mul-tivariate Cox regression analysis showed that the intratumoral FSTL1 expression conferred a favorable independent prognosis with a hazard ratio of 0.325(95%confidence interval 0.118-0.894).HIF-2αexpression was negatively cor-related with FSTL1 expression in ccRCC specimens(r=−0.229,P=0.044).Intratumoral expression of HIF-2α,rather than HIF-1α,significantly predicted an unfavorable prognosis in ccRCC(log-rank,P=0.038).Conclusions:FSTL1 plays a tumor suppression role possibly via repressing the NF-κB and HIF-2αsignaling pathways.To increase FSTL1 expression might be a candidate therapeutic strategy for metastatic ccRCC.