Abstract 556: The glucocorticoid axis serves as biomarkers for supraphysiological androgen therapy response in enzalutamide-resistant prostate cancer

Abstract Next-generation androgen receptor (AR) antagonist, like enzalutamide (Enz) has revolutionized the treatment of castration-resistant prostate cancer (CRPC), the lethal form of the disease, by effectively suppressing the androgen axis. However, resistance to Enz eventually develops in nearly all patients. Recent studies indicate that increased glucocorticoid receptor (GR) expression contributes to Enz resistance. Our prior work in prostate cancer models and patient tissues suggests that Enz decreases 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2, inactivates cortisol) and increases hexose-6-phosphate dehydrogenase (H6PD, promotes cortisol production) expression in tumor, which then sustains high levels of cortisol, leading to overstimulation of GR and resistance to Enz. Collectively, the glucocorticoid axis, including GR expression level and cortisol concentration controlled by 11β-HSD2 and H6PD, plays a critical role in Enz-resistant CRPC. Studies suggest AR activation reduces GR expression in PC, and SPA counteracts glucocorticoid-induced muscle atrophy, indicating AR activation inhibits GR functions in various contexts. Patient and mouse studies show that supraphysiologic androgen (SPA) reverses Enz resistance, and ∼30% of patients respond to SPA; however, we lack a biomarker that identifies which patients will respond. A clinical study revealed that Enz treatment increases serum cortisol by suppressing11β-HSD2 expression, which is correlated with patient blood pressure. Taking all these together, we hypothesized that SPA reverses Enz through attenuation of the GR pathway by affecting GR expression and cortisol level. By using qPCR, immunoblot, high-performance liquid chromatography, and live cell imaging analysis, we observed that SPA decreases GR expression, accelerates cortisol metabolism by decreasing H6PD and increasing 11β-HSD2, and suppresses glucocorticoid-induced cell growth in Enz-resistant prostate cancer cell lines. Next, to further test our hypothesis that the glucocorticoid axis and blood pressure can serve as biomarkers for SPA therapy response. We will first confirm our cell level findings with cell-derived and patient-derived xenograft studies, then by collaborating with physician scientists, we will further evaluate the biomarker roles of the glucocorticoid axis for SPA therapy response in Enz-resistant prostate cancer by analyzing serum cortisol, expression of GR, H6PD, and 11β-HSD2 in circulating tumor cells, and blood pressure of patients who have undergone SPA treatment. This research holds the promise of not only confirming and solidifying both SPA's clinical benefits and the GR pathway's clinical significance in Enz resistance but also setting the foundation for our goal of developing the first non-invasive biomarkers for SPA therapy in patients with disease resistant to Enz. Citation Format: Jianneng Li, Zhichao Liu, Mallory Sands, Sam Adams, Jihaeng Lee, Mae Wang, TJ Walsh, Matthew Haerens, Michael Li, Leo Leon, Adriana Zablah. The glucocorticoid axis serves as biomarkers for supraphysiological androgen therapy response in enzalutamide-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 556.