No abstract

Human androgen receptor (AR) is a hormone-activated transcription factor that is an important drug-target in the treatment of prostate cancer. Current small molecule AR-antagonists, such as enzalutamide, compete with androgens that bind to the steroid binding pocket of the AR ligand binding domain (LBD). In castration-resistant prostate cancer (CRPC), drug-resistance can manifest through AR-LBD mutations that convert AR-antagonists into agonists, or by expression of AR-variants lacking the LBD. Such treatment resistance underscores the importance of novel ways of targeting the AR. Previously, we reported the development a series of small molecules that were rationally designed to selectively target the AR DNA binding domain (DBD) and, hence, to directly interfere with AR-DNA interactions. In the current work we have confirmed that the lead AR DBD inhibitor indeed directly interacts with the AR-DBD and tested that substance across multiple clinically relevant CRPC cell lines. We have also performed a series of experiments that revealed that genome-wide chromatin binding of AR was dramatically impacted by the lead compound (although with lesser effect on AR variants). Collectively, these observations confirm the novel mechanism of anti-androgen action of the developed AR-DBD inhibitors, establishing proof-of-principle for targeting DNA-binding domains of nuclear receptors in endocrine cancers.

Background SARS‐CoV‐2 has massively changed the care situation in hospitals worldwide. Although tumour care should not be affected, initial reports from European countries were suggestive for a decrease in skin cancer during the first pandemic wave and only limited data are available thereafter. Objectives The aim of this study was to investigate skin cancer cases and surgeries in a nationwide inpatient dataset in Germany. Methods Comparative analyses were performed in a prepandemic (18 March 2019 until 17 March 2020) and a pandemic cohort (18 March 2020 until 17 March 2021). Cases were identified and analysed using the WHO international classification of diseases codes (ICDs) and process key codes (OPSs). Results Comparing the first year of the pandemic with the same period 1 year before, a persistent decrease of 14% in skin cancer cases ( n = 19 063) was observed. The largest decrease of 24% was seen in non‐invasive in situ tumours ( n = 1665), followed by non‐melanoma skin cancer (NMSC) with a decrease of 16% ( n = 15 310) and malignant melanoma (MM) with a reduction of 7% ( n = 2088). Subgroup analysis showed significant differences in the distribution of sex, age, hospital carrier type and hospital volume. There was a decrease of 17% in surgical procedures ( n = 22 548), which was more pronounced in minor surgical procedures with a decrease of 24.6% compared to extended skin surgery including micrographic surgery with a decrease of 15.9%. Conclusions Hospital admissions and surgical procedures decreased persistently since the beginning of the pandemic in Germany for skin cancer patients. The higher decrease in NMSC cases compared to MM might reflect a prioritization effect. Further evidence from tumour registries is needed to investigate the consequences of the therapy delay and identify the upcoming challenges in skin cancer care.