Novel therapeutics dual targeting intracrine androgen synthesis and AR for advanced prostate cancer

ABSTRACT Continued expression of androgen receptor (AR) and its variants, such as AR-V7, despite AR targeted therapy contributes to treatment resistance and cancer progression in advanced CRPC patients. This highlights the need for new strategies to block continued AR signaling. Aldo-keto reductase family 1 member C3 (AKR1C3) is one of the most important genes involved in androgen synthesis and metabolism. Activity of this enzyme cannot be inhibited by abiraterone. Both AR/AR-V7 and AKR1C3 play key roles in cancer progression and driving resistance to current therapies. Therefore, inhibition of both AR/AR-V7 and AKR1C3 would be an ideal strategy for treating advanced prostate cancer (PCa). We have designed a novel strategy to simultaneously target the AR/AR-V7 and AKR1C3 pathways. We designed and synthesized a library of novel dual AKR1C3/AR/AR-variant inhibitors, called LX, according to structure-based computer modeling. Of the LX compounds, LX-1 had the greatest effect at reducing cell number, AR/AR variant expression, and AKR1C3 activity. RNA-seq analysis demonstrated a robust reduction in expression of AR and AR-V7 signaling genes by the selected LX. LX-1 inhibited conversion of the testosterone precursor androstenedione into testosterone in tumor cells which express high levels of AKR1C3 in a dose-dependent manner ex vivo. Furthermore, treatment with LX-1 reduced tumor growth in VCaP and LuCaP35CR PDX xenografts in vivo and decreased intratumoral testosterone. Based on these findings, the overall hypothesis is that concurrent inhibition of AR/AR variants and AKR1C3 using novel LX dual inhibitor suppresses CRPC tumor growth, overcomes resistance and improves treatment response to enzalutamide/abiraterone. This project is to further characterize LX by understanding its mechanism of action (MOA), determining its efficacy, pharmacokinetics and toxicity, and to determine their effects on the sensitivity to anti-androgen therapy with the goal to translate to future clinical development to treat advanced PCa. We hope that completion of the proposed studies will lead to the development of a new class of therapeutic agents that target both intracrine androgen synthesis and the AR signaling.