Gene expression changes following seviteronel (Sevi) treatment in HCI-009 PDXs

Triple-negative breast cancer (TNBC) is aggressive and difficult, and few targeted therapies are available to treat this patient population. The androgen receptor (AR) has emerged as a potential target in breast cancer. Newer generation AR inhibitors, such as Seviteronel (Sevi), are unique in their ability to inhibit AR both directly and by blocking upstream androgen synthesis. The purpose of this study was to investigate the pre-clinical activity of Sevi in TNBC and further explore the effectiveness of targeting both androgen biosynthesis and AR activity in combination with other downstream acting agents. AR overexpressing (AR+) TNBC cell lines, xenografts and androgen responsive patient-derived xenograft (PDX) models were using to show how effectively Sevi inhibits AR activity and cell/tumor proliferation. Single cell RNA-sequencing of the AR+ cell line MDA-MB-453 illustrated heterogeneity in AR levels and identified cell cycle pathway activation in ARHigh versus ARLow expressing cells. Combination treatment with the cell cycle CDK4/6 inhibitor abemaciclib and Sevi showed synergy in AR+ TNBC cells and increased effectiveness, compared to each drug alone, in an AR+ TNBC xenograft model. While cell cycle inhibitors have been approved for use in hormone-receptor positive breast cancer, our studies suggest that these drugs may be equally effective in AR+ TNBC cells, especially when combined with AR antagonists. Implications. These data suggest that targeting AR signaling at multiple points throughout the pathway may be an effective was to treat patients with AR+ TNBC. Overall design: HCI-009 is a TNBC PDX originally developed in the laboratory of Dr. Alana Whelm and propagated in immunodeficient NOD/SCID/gamma (NSG) mice. When tumors reached a size of approximately 100 mm3, mice were randomized and matched into treatment groups (n=4-5 mice per group). 150mg/kg/day Sevi was administered daily by oral gavage for 2 weeks.