Therapeutic effect of SARMS

Lead participant UEDIN has identified androgen target genes in primary endometrial stromal cells and obtained evidence that AR agonists can oppose oestrogen-dependent proliferation in this cell type (55). (i) In vitro cell systems developed in Edinburgh using 3D culture scaffolds will be used to evaluate the impact of a range of selective androgen receptor modulators (SARMs) alone, and in combination with E2, on cell behavior (e.g. proliferation, apoptosis, migration) and gene expression. A range of analysis methods will be used to stratify the response to different SARMs including analysis using pathway focused RT² Profiler PCR Arrays (e.g. AR signaling targets, EMT, cell cycle), qRTPCR, reporter assays, Westerns, immunohistochemistry). To test whether SARMs are capable of activating the mouse Ar we will quantify their ability to induce expression of a luciferase reporter gene in female ‘androgen reporter mice’ (68). Uterine tissues will be retrieved from the mice following an injection of BrDu and both Ar expression and cell proliferation determined. We will assess the impact of SARMs identified as having the most potent impact on uterine cells using our in house model of mouse endometriosis (66): endpoints will include lesion size and pain scores. In addition, UEDIN will identify DCA-responsive proteins/functional pathways as future candidate targets for therapeutic development.