Saturday, August 13, 2022
8/13/2022
Enzalutamide and abiraterone are initially effective for the treatment of castration-resistant prostate cancer (CRPC). However, resistance to both drugs occurs frequently through mechanisms which are incompletely understood. Intratumoral androgen biosynthesis is well characterized as one of the important mechanisms of castration resistant prostate cancer (CRPC). Many enzymes are involved in androgen synthesis including CYP17A1 and steroid sulfatase (STS). CYP17A1 can be inhibited by abiraterone (Abi) in clinical treatments. However, androgen synthesis inhibition by abiraterone is incomplete, suggesting sustained steroidogenesis in addition to CYP17A1 contributes to resistance. Dehydroepiandrosterone-SO4 (DHEAS) is present at plasma concentrations up to 500 times higher than testosterone in prostate cancer patients and can potentially be converted via STS into desulphated DHEA and then into androgens in prostate cancer cells. Conversion of circulated DHEAS to DHEA by STS is believed to be an alternative source of androgen which cannot be inhibited by abiraterone. Thus, STS may contribute to this sustained androgen production even in the presence of abiraterone. Our preliminary data demonstrates that STS is overexpressed in CRPC cells. Overexpression of STS increases cell growth and confers resistance to anti-androgens. In addition, we have identified several novel small molecule inhibitors of STS, namely, SI. Targeting STS activity by the SI inhibits STS activity, suppresses AR transcriptional activity, reduces the growth of resistant CRPC cells, and enhances enzalutamide treatment in vitro and in vivo. These results suggest that STS plays a critical role in CRPC progression and that targeting STS could be a viable strategy to treat advanced CRPC. The objectives of this proposal are to determining the roles of STS and targeting this enzyme with novel inhibitors to improve anti- androgen treatment response. In aim 1, we will determine the roles of STS in the development of resistance to enzalutamide. In aim 2, we will characterize STS and its steroid metabolites in CRPC, and in aim 3 we will determine the potential of targeting STS to overcome treatment resistance. This proposal will establish STS as one of the important mechanisms of progression and resistance to next-generation anti-androgen therapy, and develop novel STS inhibitors to target STS activity to potentially inhibit CRPC growth and reverse treatment resistance.
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