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Most prostate cancers express the androgen receptor (AR), and tumor growth and progression are facilitated by exceptionally low levels of systemic or intratumorally produced androgens. Thus, absolute inhibition of the androgen signaling axis remains the goal of current therapeutic approaches to treat prostate cancer (PCa). Paradoxically, high dose androgens also exhibit considerable efficacy as a treatment modality in patients with late-stage metastatic PCa. Here we show that low levels of androgens, functioning through an AR monomer, facilitate a non-genomic activation of the mTOR signaling pathway to drive proliferation. Conversely, high dose androgens facilitate the formation of AR dimers/oligomers to suppress c-MYC expression, inhibit proliferation and drive a transcriptional program associated with a differentiated phenotype. These findings highlight the inherent liabilities in current approaches used to inhibit AR action in PCa and are instructive as to strategies that can be used to develop new therapeutics for this disease and other androgenopathies., (© 2024. The Author(s).)

Purpose: HOXB13 is an androgen receptor (AR) coregulator specifically expressed in cells of prostatic lineage. We sought to associate circulating tumor cell (CTC) HOXB13 expression with outcomes in men with mCRPC treated with abiraterone or enzalutamide., Experimental Design: We conducted a retrospective analysis of the multicenter prospective PROPHECY trial of mCRPC men (NCT02269982, n = 118) treated with abiraterone/enzalutamide. CTC detection and HOXB13 complementary DNA (cDNA) expression was measured using a modified Adnatest, grouping patients into 3 categories: CTC 0 (undetectable); CTC+ HOXB13 CTC low (<4 copies); or CTC+ HOXB13 CTC high. The HOXB13 threshold was determined by maximally selected rank statistics for prognostic associations with overall survival (OS) and progression-free survival (PFS)., Results: We included 102 men with sufficient CTC HOXB13 cDNA, identifying 25%, 31%, and 44% of patients who were CTC 0, CTC+ HOXB13 low, and CTC+ HOXB13 high, respectively. Median OS were 25.7, 27.8, and 12.1 months whereas the median PFS were 9.0, 7.7, and 3.8 months, respectively. In subgroup analysis among men with CellSearch CTCs ≥5 copies/mL and adjusting for prior abi/enza treatment and Halabi clinical risk score, the multivariate HR for HOXB13 CTC detection was 2.39 (95% CI, 1.06-5.40) for OS and 2.78 (95% CI, 1.38-5.59) for PFS, respectively. Low HOXB13 CTC detection was associated with lower CTC PSA, PSMA, AR-FL, and AR-V7 detection, and more liver/lung metastases (41% vs. 25%)., Conclusions: Higher CTC HOXB13 expression is associated with AR-dependent biomarkers in CTCs and is adversely prognostic in the context of potent AR inhibition in men with mCRPC., (©2024 American Association for Cancer Research.)

This study aimed to examine the demographic characteristics of pregnant women in a Healthy Start program who are presumed eligible for the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC), but who have not yet applied for WIC benefits. We used a cross sectional evaluation of data collected from pregnant women (n=203) participating in a Healthy Start program. Data came from surveys administered at enrollment in the Healthy Start program from July 15th, 2019 until January 14th, 2022. The primary outcome was WIC application status, which was determined by whether the woman had applied or was receiving benefits at the time of enrollment. Covariates included race/ethnicity, marital status, insurance, education, income, age, employment, and having previous children/pregnancies. Fisher exact tests and logistic regression were used to examine associations. Approximately 65% of women had not yet applied for WIC benefits. Marshallese women (80.9%) and other NHPI women (80.0%) had the highest need for assistance. In adjusted analyses, White women (p = 0.040) and Hispanic women (p = 0.005) had lower rates of needing assistance applying for WIC than Marshallese women. There were higher rates of needing assistance in applying for women with private insurance or with no insurance and for those with higher incomes. Nearly two out of every three pregnant women who were eligible for WIC had not yet applied for benefits. The findings highlight the need for outreach for all populations that may be eligible, particularly among racial/ethnic minorities and those with higher incomes., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Despite continued interest in the development of nonsteroidal estrogens and antiestrogens, there are only a few chemotypes of estrogen receptor ligands. Using targeted screening in a ligand sensing assay, we identified a phenolic thieno[2,3- d ]pyrimidine with affinity for estrogen receptor α. An efficient three-step synthesis of the heterocyclic core and structure-guided optimization of the substituents resulted in a series of potent nonsteroidal estrogens. The chemical tractability of the thieno[2,3- d ]pyrimidine chemotype will support the design of new estrogen receptor ligands as therapeutic hormones and antihormones., Competing Interests: The authors declare no competing financial interest., (© 2022 American Chemical Society.)