Significance: Using an unbiased forward mutagenesis screen, we were able to successfully identify candidate genes that drive advanced and metastatic prostate cancer (CaP). Alterations of peroxisome proliferator-activated receptor gamma (PPARG), encoding a regulator crucial of lipid metabolism, appear to play a role in the development of metastatic CaP in both humans and mice.

The incorporation of transition metal catalysts to the bioorthogonal toolbox has opened the possibility of producing supra-stoichiometric amounts of xenobiotics in living systems in a non-enzymatic fashion. For medical use, such metals could be embedded in implantable devices (i.e. heterogeneous catalyst) to “synthesize” drugs in desired locations (e.g. in a tumour) with high specificity and for extended periods of time, overcoming the useful life limitations of current local therapy modalities directed to specific organ sites (e.g. brachytherapy, controlled release systems). To translate this approach into a bona fide therapeutic option, it is essential to develop clinically-accessible implantation procedures and to understand and validate the activation process in relevant preclinical models. Herein we report the development of a novel Pd-activatable precursor of the red-fluorescent drug doxorubicin and Pd devices of optimized size and activity. Screening in state-of-the-art cancer models provided fundamental insights into the insertion protocols, safety and stability of the devices and into the prodrug distribution profile before and after activation.

Obesity and aggressive prostate cancer (PC) may be linked, but how local peri-prostatic fat relates to tumour response following androgen deprivation therapy (ADT) is unknown. To test if peri-prostatic fat volume (PPFV) predicts tumour response to ADT. We performed a retrospective study on consecutive patients receiving primary ADT. From staging pelvic magnetic resonance imaging scans, the PPFV was quantified with OsirixX 6.5 imaging software. Statistical (univariate and multivariate) analysis were performed using R Version 3.2.1. Of 224 consecutive patients, 61 with advanced (≥T3 or N1 or M1) disease had (3-mm high resolution axial sections) pelvic magnetic resonance imaging scan before ADT. Median age=75 yr; median PPFV=24.8cm3 (range, 7.4-139.4cm3). PPFV was significantly higher in patients who developed castration resistant prostate cancer (CRPC; n=31), with a median of 37.9cm3 compared with 16.1cm3 (p <0.0001, Wilcoxon rank sum test) in patients who showed sustained response to ADT (n=30). Multivariate analysis using Cox proportional hazards models were performed controlling for known predictors of CRPC. PPFV was shown to be independent of all included factors, and the most significant predictor of time to CRPC. Using our multivariate model consisting of all known factors prior to ADT, PPFV significantly improved the area under the curve of the multivariate models receiver operating characteristic analysis. The main study limitation is a relatively small cohort to account for multiple variables, necessitating a future large-scale prospective analysis of PPFV in advanced PC. PPFV quantification in patients with advanced PC predicts tumour response to ADT. The amount of fat around the prostate predicts prostate cancer response to hormone treatment.

Androgen deprivation therapy (ADT) is the standard of care for treatment of nonresectable prostate cancer. Despite high treatment efficiency, most patients ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we performed a comparative proteomic analysis of three in vivo, androgen receptor (AR)-responsive orthograft models of matched hormone-naïve prostate cancer and CRPC. Differential proteomic analysis revealed that distinct molecular mechanisms, including amino acid (AA) and fatty acid metabolism, are involved in the response to ADT in the different models. Despite this heterogeneity, Schlafen family member 5 (SLFN5) was identified as an AR-regulated protein in CRPC. SLFN5 expression was high in CRPC tumors and correlated with poor patient outcome. In vivo, SLFN5 depletion strongly impaired tumor growth in castrated conditions. Mechanistically, SLFN5 interacted with ATF4 and regulated the expression of LAT1, an essential AA transporter. Consequently, SLFN5 depletion in CRPC cells decreased intracellular levels of essential AA and impaired mTORC1 signaling in a LAT1-dependent manner. These results confirm that these orthograft models recapitulate the high degree of heterogeneity observed in patients with CRPC and further highlight SLFN5 as a clinically relevant target for CRPC. Significance: This study identifies SLFN5 as a novel regulator of the LAT1 amino acid transporter and an essential contributor to mTORC1 activity in castration-resistant prostate cancer.

Despite the clinical benefit of androgen‐deprivation therapy (ADT), the majority of patients with advanced prostate cancer (PCa) ultimately develop lethal castration‐resistant prostate cancer (CRPC). In this study, we identified thioesterase superfamily member 6 (THEM6) as a marker of ADT resistance in PCa. THEM6 deletion reduces in vivo tumour growth and restores castration sensitivity in orthograft models of CRPC. Mechanistically, we show that the ER membrane‐associated protein THEM6 regulates intracellular levels of ether lipids and is essential to trigger the induction of the ER stress response (UPR). Consequently, THEM6 loss in CRPC cells significantly alters ER function, reducing de novo sterol biosynthesis and preventing lipid‐mediated activation of ATF4. Finally, we demonstrate that high THEM6 expression is associated with poor survival and correlates with high levels of UPR activation in PCa patients. Altogether, our results highlight THEM6 as a novel driver of therapy resistance in PCa as well as a promising target for the treatment of CRPC.

Metastatic castration‐resistant prostate cancer (mCRPC) is a lethal form of treatment‐resistant prostate cancer and poses significant therapeutic challenges. Deregulated receptor tyrosine kinase (RTK) signalling mediated by loss of tumour suppressor Sprouty2 (SPRY2) is associated with treatment resistance. Using pre‐clinical human and murine mCRPC models, we show that SPRY2 deficiency leads to an androgen self‐sufficient form of CRPC. Mechanistically, HER2‐IL6 signalling axis enhances the expression of androgen biosynthetic enzyme HSD3B1 and increases SRB1‐mediated cholesterol uptake in SPRY2‐deficient tumours. Systemically, IL6 elevated the levels of circulating cholesterol by inducing host adipose lipolysis and hepatic cholesterol biosynthesis. SPRY2‐deficient CRPC is dependent on cholesterol bioavailability and SRB1‐mediated tumoral cholesterol uptake for androgen biosynthesis. Importantly, treatment with ITX5061, a clinically safe SRB1 antagonist, decreased treatment resistance. Our results indicate that cholesterol transport blockade may be effective against SPRY2‐deficient CRPC.