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The circadian system, a vital temporal regulator influencing physiological processes, has implications for cancer development and treatment response. Our study assessed circadian timing’s impact on whole-brain radiotherapy outcomes in brain metastases for personalized cancer therapy insights. The aim of the study was to evaluate circadian influence on radiation treatment timing and its correlation with clinical outcomes and to identify patient populations benefiting from interventions synchronizing circadian rhythms, considering subgroup differences and potential disparities. An IRB-approved retrospective analysis of 237 patients undergoing whole-brain radiotherapy for brain metastases (2017–2021), receiving over 80% of treatments in the morning or afternoon, was performed. Survival analyses utilized Kaplan–Meier curves. This was a single-institution study involving patients receiving whole-brain radiotherapy. Demographic, disease, and socioeconomic parameters from electronic medical records were collected. Morning treatment (n = 158) showed a trend toward improved overall survival vs. afternoon (n = 79); the median survival was 158 vs. 79 days (p = 0.20, HR = 0.84, CI95% 0.84–0.91). Subgroup benefits for morning treatment in females (p = 0.04) and trends in controlled primary disease (p = 0.11) and breast cancer metastases (p = 0.08) were observed. Black patients exhibited diminished circadian influence. The present study emphasized chronobiological factors’ relevance in brain metastases radiation therapy. Morning treatment correlated with improved survival, particularly in specific subgroups. Potential circadian influence disparities were identified, laying a foundation for personalized cancer therapy and interventions synchronizing circadian rhythms for enhanced treatment efficacy.

Abstract The constitutively active androgen receptor (AR) splice variant, AR-V7, plays an important role in resistance to androgen deprivation therapy in castration resistant prostate cancer (CRPC). Studies seeking to determine whether AR-V7 is a partial mimic of the AR, or also has unique activities, and whether the AR-V7 cistrome contains unique binding sites have yielded conflicting results. One limitation in many studies has been the low level of AR variant compared to AR. Here, LNCaP and VCaP cell lines in which AR-V7 expression can be induced to match the level of AR, were used to compare the activities of AR and AR-V7. The two AR isoforms shared many targets, but overall had distinct transcriptomes. Optimal induction of novel targets sometimes required more receptor isoform than classical targets such as PSA. The isoforms displayed remarkably different cistromes with numerous differential binding sites. Some of the unique AR-V7 sites were located proximal to the transcription start sites (TSS). A de novo binding motif similar to a half ARE was identified in many AR-V7 preferential sites and, in contrast to conventional half ARE sites that bind AR-V7, FOXA1 was not enriched at these sites. This supports the concept that the AR isoforms have unique actions with the potential to serve as biomarkers or novel therapeutic targets.

Cryptochrome 1 (CRY1) is a transcriptional coregulator associated with the circadian clock. Here the authors reveal that CRY1 is hormone-regulated, stabilized by genomic insult, and promotes DNA repair and cell survival through temporal transcriptional regulation.