Targeting the Inflammation as a Novel Therapy for Neuroendocrine Prostate Cancer Determined by Zbtb46

Androgen receptor (AR) targeting is the most important therapeutic strategy for treating prostate cancer. However, most tumors progress to castration-resistant prostate cancer (CRPC) under androgen deprivation therapy (ADT) and increase inflammatory response favoring prostate cancer proliferation and metastasis. We previously reported that a novel tumor promoter, ZBTB46, is activated in androgen-deprived prostate cancer with a variety of metastatic properties, and here we propose that ZBTB46 associates with prostaglandin-endoperoxide synthase (PTGS) 1 and contributes to inflammatory response and neuroendocrine (NE) differentiation of prostate cancer cells. Overexpression of ZBTB46 decreases the sensitivity of combined enzalutamide and the PTGS1 inhibitor; however, knockdown of ZBTB46 induces the sensitivity of the PTGS1 inhibitor and reduces tumor malignancy. ZBTB46 induces abundant prostate neuroendocrine (NEPC) markers and positively associates with PTGS1 stimulation in prostate cancer cells. We will further study the mechanisms of why ZBTB46 expression is stimulated by the loss of the AR signaling pathway and activated in the inflammatory response of prostate cancer cells. We have demonstrated that inhibition of an AR-activated gene, SAM-pointed domain containing ETS transcription factor (SPDEF), is responsible for ZBTB46 stimulation and is associated with NEPC transformation following androgen deprivation. We will further study novel insights into the role of the SPDEF-ZBTB46 axis in NE differentiation of the prostate and establish a causal link between the NEPC-promoting effects of ZBTB46 and the inflammatory response after androgen withdrawal. Our preliminary results suggest that induction of ZBTB46 resulting in increased PTGS1 expression is associated with NEPC differentiation linked to dysregulation of the AR-SPDEF pathway. Our goal of novel diagnostic approaches seeks to identify and utilize targeted inflammatory response components with increased selectivity and efficacy in NEPC patient treatment. Therefore, the following investigations are proposed: Specific Aim I: Determine the role of ZBTB46 in inducing NE differentiation and investigate the molecular basis of ZBTB46 being regulated by the AR-SPDEF axis in NEPC cells. Specific Aim II: Identify inflammatory cytokines that associate with ADT-induced ZBTB46 and define the role of ZBTB46 that contributes to inflammatory response of NEPC. Specific Aim III: Explore the therapeutic target of ZBTB46 by a combination of anti-inflammatory and ADT and determine the potential diagnostic marker of ZBTB46 in response to ADT resistance of NEPC patients.