AR underexpression

Higher AR expression levels are associated with higher grade disease and histopathologic features predicting poorer prognosis in lower grade gliomas. Higher gene expression in LGG patients is correlated with poor prognosis but not in the glioblastoma cohort suggesting saturated expression/functions of AR in glioblastoma.

As a potential suppressor for ER positive BCs, negative or low AR expression might be associated with higher proliferation rate and recurrence risk in ER positive BCs. Further detailed study is required.

DKN-01 600 mg was well tolerated. DKK1 blockade has modest anti-tumor activity as a monotherapy for mCRPC. Anti-tumor activity was observed in the combination cohorts, but the response duration was limited. DKK1 expression in the majority of mCRPC is low and did not clearly correlate with anti-tumor activity of DKN-01 plus docetaxel.

Most 2 generation anti-androgens confer radiosensitization in AR+ TNBC models with cellular localization changes of AR noted after RT. The known structural differences amongst 2 generation anti-androgens may account for differences in radiosensitization noted. Furthermore, AR-mediated radioresistance may be due, at least in part, to downstream MAPK/ERK signaling. This work builds on the mechanistic understanding of AR-mediated radioresistance in AR+ TNBC and may expose vulnerabilities to overcome resistance to combination treatment with AR inhibition and RT.

EV-H19 may negatively correlate with AR-signaling activity and could be a marker to diagnose ARAT-resistance among CRPC patients.

Inhibition with the 2 nd generation anti-androgens enzalutamide and apalutamide is sufficient to radiosensitize AR+ TNBC models (rER: 1.34-1.41); while darolutamide had no effect on radiosensitivity (rER: 0.96-1.11). Most 2 nd generation anti-androgens confer radiosensitization in AR+ TNBC models with cellular localization changes of AR noted after RT. The known structural differences amongst 2 nd generation anti-androgens may account for differences in radiosensitization noted. Furthermore, AR-mediated radioresistance may be due, at least in part, to downstream MAPK/ERK signaling.

Our study findings suggest that HER2-positive breast cancer patients with high AR expression levels may achieve higher pCR rates when treated with neoadjuvant dual-blocked therapy. Overall, our results support the idea that AR expression levels have a significant correlation with pCR rates in HER2-positive breast cancer patients receiving this particular form of treatment.

A lower preoperative PSA level was an independent predictive factor for a favorable pathologic response. Moreover, the expression status of AR and Ki-67 in biopsy specimens were associated with differential pathologic response to NCHT, and AR low/Ki-67 high was also associated with favorable response but warrants further evaluation in this patient subgroup and future trial clinical trial design.

Multigene, RNA-based low AR expression is associated with aggressive disease characteristics as well as DNA repair defects and immune phenotypes, suggesting plausible precision therapies for AR-low, ER-negative patients.

In organoids derived from patients with neuroendocrine prostate cancer, therapeutic inhibition of VEGF binding to NRP2 using a high-affinity humanized mAb suitable for clinical use also diminished PD-L1 expression and caused a substantial increase in immune-mediated tumor cell killing, consistent with the animal studies. These findings provide justification for the initiation of clinical trials using this function-blocking NRP2 mAb in prostate cancer, especially for patients with aggressive disease.

18 F-PSMA-1007 PET/CT was excellent in detecting primary tumors of all GS in the prostate gland. Some primary tumors showed a reciprocal pattern of 18 F-PSMA-1007 and 18 F-FDG uptake which were mostly large ductal type with low AR expression. Further studies are needed to see whether tumors with 18 F-FDG uptake may predict treatment resistance to androgen deprivation therapy and PSMA RLT.

The results of our study demonstrate AR expression in a wide range of cancers. AR expression occurs most frequent in cancers of the prostate, breast, and ovary, but can be found in many types of non-prostate and non-gynecological neoplasms. The poor prognosis of breast and kidney cancers with reduced AR expression argues against a tumor promoting role of AR in these tumor types.

These data suggest that lineage plasticity may contribute to heterogeneity of CK19 positive HCC, which in turn carry clinical implications regarding new treatment strategies for treatment of HCC with highly recurrence.

Snail expression was associated with the expressions of CCL20 and CCR6. The xenograft study showed that the anti-CCL20 antibody significantly inhibited snail expression, thereby suggesting a new therapeutic approach to castration-resistant prostate cancer with inhibition of the axis between CCL20 and CCR6.

However, both a selective AR agonist (RAD140) and an AR inhibitor (enzalutamide, ENZ) have shown a therapeutic effect on ER+ breast cancer, so the potential for clinical application of AR-targeting therapy for ER+ breast cancer is still in dispute. In contrast, RAD140 activated AR signaling and suppressed AR-high tumor growth by deregulating ERα expression and blocking ERα function. Overall, analysis of the dynamic efficacies and outcomes of AR agonist and antagonist in the presence of different AR and ERα levels reveals regulators of response and supports the clinical investigation of ENZ in selected ER+ tumors with a low AR/ER ratio and AR agonists in tumors with a high AR/ER ratio.

The expression of AR in our sample was similar to the expression in populations of European descent. We found statistically significant differences in age at diagnosis and Ki67 expression according to AR expression.

We found that eukaryotic translation initiation factor (EIF) 5A2, an elongation factor that induces epithelial-to-mesenchymal transition (EMT) in PCa cells, was significantly upregulated after 5α-dihydrotestosterone (DHT) stimulation and downregulated after anti-androgen bicalutamide treatment in PCa cells with high AR expression, but not in cells with low AR expression...Moreover, in vivo study, Luciferase signals from the lungs of the eIF5A2 plasmid group indicated higher metastasis ability, and the eIF5A2 siRNA group had lower metastasis ability. Our results suggest that AR positively regulates eIF5A2 expression in androgen-dependent cells, and stimulation of AR expression and signaling in prostate tumors promotes PCa metastasis by EMT induction and upregulation of eIF5A2.

Further, expression of these factors was also associated with decreased time to biochemical relapse and decreased progression-free survival. Our studies reveal the key metabolites fueling castration resistant progression in the context of a partial or complete loss of AR dependence.

T-lymphocyte infiltration in hormone-naïve disease associates with androgen-independent driven disease and provides possible therapeutic targets to reduce transformation from hormone-naïve to castrate-resistant disease.

The present study reports that patients with CRPC expressing high levels of nuclear IKKα or cytoplasmic p-IKKα S180, which associated with a lower time to death from recurrence, may benefit from IKKα inhibitors.