However, existing orthosteric ligand-binding pocket (LBP) antagonists [e.g., enzalutamide (ENZ)] encounter significant obstacles due to resistance-conferring mutations in the LBP. Multiple short- and/or long-range BF3→AF2 and LBP→AF2 signaling transition pathways are involved, such as F673→Y834→L722→L812→L744→V746→L873→ENZ→L880/V889/V891. These mechanistic insights establish the foundation for developing novel AR BF3 antagonist and LBP-BF3 combination therapies, suggesting a promising avenue for enhancing the efficacy and overcoming the resistance in castration-resistant prostate cancer treatment.

In this final OS analysis, CR1447 was associated with an OS in line with other ET agents in patients with metastatic ER-positive, HER2-negative breast cancer who had received no more than 1 prior line of ET. Therapy was well tolerated with no treatment-related grade 3 to 5 toxicities.

However, clinical studies of androgen receptor antagonism have yielded minimal success. In this review, we explore the tumor suppressor role of androgen receptor in bladder cancer and discuss how it might be harnessed therapeutically.

  Lower levels of testosterone were related to lower rates of erectile function recovery at the end of 24 months after RRP, in addition to conferring higher rates of BCR and higher ISUP grades in biopsy.  Furthermore, patients with total testosterone < 300 ng/dL had higher expression of AR, but no difference in BCR rates.

Mutational analysis of AR/ER is ongoing to determine benefit of this treatment in specific subgroups. CR1447 might be a candidate drug to combine with other agents (CDK4/6 inhibitors or other targeted therapies).

Interestingly, pretreating LNCaP and C4-2 cells with either androgen or the androgen receptor (AR) antagonist enzalutamide mediates resistance to this immunogenic attack...The obtained data suggest that the conditioned media from PCa treated cells does not influence a measurable lymphocyte-mediated apoptosis. However, analysing clonal expansion of activated lymphocytes, the androgen-derived conditioned media suppresses lymphocyte proliferation/expansion suggesting inhibition of onco-immunological activity by pretreatment of PCa cells with AR ligands.

P2, N=29, Terminated, Swiss Group for Clinical Cancer Research | Trial completion date: Jun 2027 --> Oct 2022 | Active, not recruiting --> Terminated; The SAKK board decided to prematurely end the life-long follow-up of the trial SAKK 21/12, as 90% of the patients have died.

Our results also show the differences and equivalences between the different agonists, in addition to evaluating the difference between the DHT ligand in complex with the wild-type and mutant receptor, presenting the main amino acid residues that involve the interaction with the ligands. The computational methodology used proves to be an operative and sophisticated choice to help in the search for pharmacological agents for various therapies that have androgen as a target.

Computational modelling revealed that helix 12 of AR undergoes a characteristic shift upon VPC14368 binding causing the agonistic behaviour. Based on the obtained structural data we then designed derivatives of VPC14368 to successfully eliminate the cross-reactivity towards the AR ABS, while maintaining significant anti-AR DBD potency.

The present study established a novel in vitro 3D microenvironment model that simulated the bone microenvironment of CRPC, and evaluated the drug susceptibility of ARATs and the efficacy of the combination of abiraterone and dutasteride. The bone microenvironment model of the present study is unique and useful for evaluating new drug susceptibility testing in prostate cancer cells. This model may help to reveal the unknown mechanisms underlying micro- to clinical bone metastasis in prostate cancer.