The androgen receptor (AR) is a major driver of prostate cancer (PCa) and a key therapeutic target for AR inhibitors (ie, Enzalutamide). However, Enzalutamide only inhibits androgen‐dependent AR signaling, enabling intrinsic AR activation via androgen‐independent pathways, leading to aggressive castration‐resistant PCa (CRPC). We investigated the ability of novel anti‐cancer agents, Dp44mT and DpC, to overcome androgen resistance. The effect of Dp44mT and DpC on androgen‐dependent and independent AR signaling was assessed in androgen‐dependent and ‐independent PCa cells using 2D‐ and 3D‐tissue culture. The clinically trialed DpC was then examined in vivo and compared to Enzalutamide. These agents uniquely promote AR proteasomal degradation and inhibit AR transcription in PCa cells via the upregulation of c‐Jun, potently reducing the AR target, prostate‐specific antigen (PSA). These agents also inhibited the activation of key molecules in both androgen‐dependent and independent AR signaling (ie, EGFR, MAPK, PI3K), which promote CRPC. The clinically trialed DpC also significantly inhibited PCa tumor growth, AR, and PSA expression in vivo, being more potent than Enzalutamide. DpC is a promising candidate for a unique, structurally distinct generation of AR inhibitors that simultaneously target both androgen‐dependent and independent arms of AR signaling. No other therapies exhibit such comprehensive and potent AR suppression, which is critical for overcoming the development of androgen resistance.

We design and synthesize EpCAM antibodies with Fc-domain site-specific linkers that allow preferential alignment when coated on microfluidic devices for capturing circulating tumor cells (CTCs) from colorectal cancer patients. The aligned coating is shown to increase the capture efficiency of CTCs and microemboli by 1.6 and 3.0-fold, respectively (both P < 0.05).

Background and Purpose: Breast cancer is the leading cause of death in women worldwide, with resistance to current therapeutic strategies, including tamoxifen, causing major clinical challenges and leading to more aggressive and metastatic disease. To address this, novel strategies that can inhibit the mechanisms responsible for tamoxifen resistance need to be assessed. Experimental Approach: We examined the effect of the novel, clinically-trialled, thiosemicarbazone anti-cancer agent, DpC, and its potential as a combination therapy with the clinically used estrogen receptor (ER) antagonist, tamoxifen, using both tamoxifen-resistant and -sensitive, human breast cancer cells (MDA-MB-453, MDA-MB-231 and MCF-7) in 2D and 3D cell-culture. Synergy was assessed using the Chou-Talalay method. The molecular and anti-proliferative effects of these agents and their combination was examined via Western blot, immunofluorescence and colony formation assays. Key Results: Combinations of tamoxifen with DpC were highly synergistic, leading to potent inhibition of cell proliferation, colony formation, and ER-α transcriptional activity. The combination also more efficiently reduced major molecular drivers of proliferation of tamoxifen-resistant cells, including c-Myc, cyclin D1, and p-AKT, while up-regulating the cell cycle inhibitor, p27, and inhibiting oncogenic phosphorylation of ER-α at Ser167. Assessing these effects using 3D cell culture further confirmed the greater effects of DpC combined with tamoxifen in reducing ER-α expression, and that of the proliferation marker, Ki-67, in both tamoxifen-sensitive and -resistant MCF-7 spheroids. Conclusions and Implications:These studies demonstrate that the synergistic combination of DpC with tamoxifen could be a promising new therapeutic strategy to overcome tamoxifen resistance in ER-positive breast cancer.

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

SummaryAlthough primary prostate cancer is largely curable, progression to metastatic disease is associated with very poor prognosis. E6AP is an E3 ubiquitin ligase and a transcriptional co-factor involved in normal prostate development. E6AP drives prostate cancer when overexpressed. Our study exposed a role for E6AP in the promotion of metastatic phenotype in prostate cells. We revealed that elevated levels of E6AP in primary prostate cancer correlate with regional metastasis and demonstrated that E6AP promotes acquisition of mesenchymal features, migration potential, and ability for anchorage-independent growth. We identified the metastasis suppressor NDRG1 as a target of E6AP and showed it is key in E6AP induction of mesenchymal phenotype. We showed that treatment of prostate cancer cells with pharmacological agents upregulated NDRG1 expression suppressed E6AP-induced cell migration. We propose that the E6AP-NDRG1 axis is an attractive therapeutic target for the treatment of E6AP-driven metastatic prostate cancer.