Metabolites of Steroidal Therapies in Hormone-Dependent Disease Regulate Response

Hormone-dependent diseases, such as prostate cancer and breast cancer, require the conversion of precursor steroids to active steroids. Prostate cancer responds initially to gonadal testosterone deprivation therapy but eventually becomes resistant as castration-resistant prostate cancer (CRPC), which is driven by tumors converting precursor steroids (e.g., DHEA and DHEA-sulfate) to testosterone and/or dihydrotestosterone. Abiraterone (administered as abiraterone acetate for oral bioavailability), a steroidal drug, is thought to block this process predominantly by inhibiting CYP17A1, an enzyme required for androgen synthesis. We have shown that abiraterone is converted in patients to D4A, a metabolite that has not previously been described, and that D4A is a more potent drug that works by blocking multiple steps along the androgen pathway. Clinical responses to abiraterone may therefore be dependent in some part on conversion to D4A. However, D4A can be metabolized further in patients and is converted by steroid-5-alpha-reductase to 5-alpha-abiraterone. In contrast to the potent antitumor effects of D4A, 5-alpha-abiraterone appears to instead stimulate the androgen receptor (AR), which is expected to promote tumor growth. Conversion of D4A to 5-alpha-abiraterone can be pharmacologically blocked by 5-alpha-reductase inhibitors, such as dutasteride and finasteride. This invention is a method of treatment whereby abiraterone or D4A is administered in conjunction with a 5-alpha-reductase inhibitor to 1) promote the accumulation of the antitumor D4A and 2) block the synthesis of the tumor stimulatory metabolite 5-alpha-abiraterone. Cell line (LNCap) and mouse xenograft study validation achieved. Michael Hansen 216-444-0386

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