Abstract B058: Exploring the oncogenic role of six-transmembrane epithelial antigen of the prostate in the context of androgen receptor signaling

Abstract

Abstract Prostate cancer is the second leading cause of death among American men, where pathogenesis is predominantly driven by dysregulation of the Androgen Receptor (AR). The current standard of care for metastatic disease includes a regime of androgen deprivation therapy (ADT) and AR antagonists, which increases survival to 24-48 months. Selective pressure of the therapy often leads to resurgence of AR activity resulting in castrate resistant disease, for which there are no curative treatment options. Moreover, once the disease has progressed to castrate resistance, AR directed therapies are no longer viable as a sole treatment option. Six-Transmembrane Epithelial Antigen of the Prostate 1-4 (STEAP) proteins are a family of ferric metalloreductases involved in maintaining iron homeostasis. STEAP expression is enriched in androgen sensitive and hormone refractory disease states, where increased expression correlates with high Gleason Score. STEAP proteins display greater intratumoral homogeneity at both primary and metastatic sites than the canonically used Prostate Specific Membrane Antigen (PSMA), indicating attractive diagnostic and therapeutic potential. Differential expression profiles have been observed among the STEAP family members depending on AR status in-vitro, suggesting a dependence on the AR signaling network. Previous literature indicates silencing of STEAPs in-vitro decreased cell viability and reduced proliferative, invasive, and migratory phenotypes; moreover in-vivo xenografts in which STEAPs are knocked down exhibited a significant reduction in tumor growth. Preliminary data suggests that treatment with Enzalutamide reduces the expression of STEAP proteins, implying a mechanistic link to the AR signaling axis. AMG509, a bispecific STEAP1-CD3 antibody, is the only STEAP directed therapeutic actively in clinical trials for prostate cancer (NCT04221542). There is limited mechanistic data regarding how STEAP directed therapies exert their anti-tumor function. Despite sharing similar architecture, localization, and biological implications, each STEAP protein retains unique functional roles within the cell. We plan to perform a systematic investigation on the oncogenic roles of individual STEAP protein in the context of AR dependent and independent prostate cancer models. In-vitro pharmacological AR manipulations will be used to evaluate changes in STEAP expression in multiple disease models. Genetic manipulations of STEAPs will be carried out under normal growth and ADT conditions to investigate the effects on growth, migration, oxidative stress, and cell cycle regulation. Given their principal role as ferric reductases, iron supplementation and iron drop-out will be examined in parallel. Novel treatment regimens will be explored using a combination of AR and STEAP directed therapeutics. Collectively, this study aims to uncover both the overlapping and distinct functions of STEAP proteins within the AR signaling axis and to illuminate their usefulness as a therapeutic target. Citation Format: Candice Bizzaro, Latese Evens, Moriah Cunningham, Jasibel Vasquez Gonzalez, Matthew Schiewer. Exploring the oncogenic role of six-transmembrane epithelial antigen of the prostate in the context of androgen receptor signaling [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B058.