The understanding of basic molecular events in the tumorigenesis and chemoresistance of EOC together with discovery of potential biomarkers may be greatly enhanced through large-scale genomic studies. In order to maximize the impact of these technologies, however, extensive validation studies are required.

Brg1 is a chromatin remodeling factor involved in mediation of a plethora of signaling pathways leading to its participation in various physiological processes both during development and in adult tissues. Among other signaling pathways, the Wnt pathway has been proposed to require Brg1 for transactivation of its target genes. Given the pivotal role of the Wnt pathway in the maintenance of normal intestinal homeostasis, we aimed to investigate the effects of Brg1 loss on the intestinal physiology. To this end, we deleted Brg1 in the murine small and large intestinal epithelia using a range of transgenic approaches. Pan-epithelial loss of Brg1 in the small intestine resulted in crypt ablation, while partial Brg1 deficiency led to gradual repopulation of the intestinal mucosa with wild-type cells. In contrast, Brg1 loss in the large intestinal epithelium was compensated by upregulation of Brm. We propose that while Brg1 is dispensable for the survival and function of the progenitor and differentiated cells in the murine intestinal epithelium, it is essential for the maintenance of the stem cell population in a tissuespecific manner.

Tumourigenesis within the intestine is potently driven by deregulation of the Wnt pathway, a process epigenetically regulated by the chromatin remodelling factor Brg1. We aimed to investigate this interdependency in an in vivo setting and assess the viability of Brg1 as a potential therapeutic target. Using a range of transgenic approaches, we deleted Brg1 in the context of Wnt-activated murine small intestinal epithelium. Pan-epithelial loss of Brg1 using VillinCreERT2 and AhCreERT transgenes attenuated expression of Wnt target genes, including a subset of stem cell-specific genes and suppressed Wnt-driven tumourigenesis improving animal survival. A similar increase in survival was observed when Wnt activation and Brg1 loss were restricted to the Lgr5 expressing intestinal stem cell population. We propose a mechanism whereby Brg1 function is required for aberrant Wnt signalling and ultimately for the maintenance of the tumour initiating cell compartment, such that loss of Brg1 in an Apc-deficient context suppresses adenoma formation. Our results highlight potential therapeutic value of targeting Brg1 and serve as a proof of concept that targeting the cells of origin of cancer may be of therapeutic relevance.

160 Background: Darolutamide is androgen-receptor (AR) inhibitor with low blood–brain barrier penetration and limited potential for clinically relevant drug–drug interactions. Darolutamide has been shown to increase overall survival in combination with androgen deprivation therapy (ADT) in patients with newly diagnosed metastatic hormone sensitive prostate cancer (PC) and, in combination with docetaxel, in men with non-metastatic castration resistant PC. This phase 2 study assessed the efficacy and safety of DARO as a monotherapy without ADT in patients with non-castrate testosterone (T) levels (≥230 ng/dL). Methods: This was a 24-wk, open-label, randomized study of patients with hormone-naïve, histologically confirmed prostate cancer (all stages, with a max of 4 metastatic lesions) requiring hormonal treatment, an ECOG PS score of 0, and a life expectancy >1 y. All patients received DARO 600 mg bid or commercially available LHRH analogue. The primary endpoint is PSA response defined as a ≥ 80% decline at week 24 relative to baseline, in the DARO study arm. The ADT arm is used as an internal control. Secondary endpoints included changes in T levels, safety/tolerability, and quality of life. Results: Among 61 men enrolled, the median (range) age was 72 y (53-86y); 49.2% had metastases; 14.8% and 62.3% had undergone prostatectomy or radiotherapy before study entry. The median (range) of PSA at baseline was 8.9 ng/mL (2.2-333.8). In the DARO arm, the evaluable population with available PSA values at baseline and week 24 consisted of 21 patients. The PSA response rate (>80% PSA decline at wk 24) was 100%, with a median (range) decrease of -99.6% (-94.3, -100) at wk 24 in the DARO arm. Serum T levels increased by a median (range) of 43.4% (5.7-144.0) at wk 24, compared with baseline. In the DARO arm, 45.2% of men reported drug-related AEs (mostly Grade 1 or 2). Most frequent treatment-emergent AEs included gynaecomastia (19.4%), fatigue (12.9%), and hot flush (12.9%). 3.1% of men experienced SAEs, none of which were drug related. HR-QoL measures and ADT arm results will be presented as internal reference. Conclusions: DARO monotherapy (600 mg bid) was associated with significant PSA response in nearly all men with hormone-naïve prostate cancer. Testosterone level changes and most common AEs (gynecomastica, fatigue and hot flush) were consistent with potent AR inhibition. Clinical trial information: NCT02972060 .