Studies of Prostate Cancer Progression after Androgen-Deprivation Therapy and Development of Cancer Immunotherapy via Anti-Inflammation Approaches

Androgen-deprivation therapy (ADT) is a standard procedure for patients encountering recurrent cancer after localized treatment; however, resistance eventually occurs and progresses to metastatic castration-resistant prostate cancer (CRPC). It is important to understand the pathological mechanisms for novel therapeutic strategies. Both the epithelial-to-mesenchymal transition (EMT) and inflammation responses are attributable to prostate cancer progression, and our previous studies have established a cellular system and demonstrated a connection between the two important cellular programs. We validated the key macrophage recruiting factor, the inflammatory cytokine CCL2, distinctly expressed in prostate cancer with mesenchymal status but not epithelial one. One direction of our planned proposal is to study the tumorigenic signaling of the EMT-inflammation communication and identify other inflammatory factors. We aim to address this issue using immune-competent syngeneic mouse tumor model. Next, one hypothesis accounting for the development of CRPC after ADT, which is designed to inhibit the AR function, is that the androgen receptor (AR) also serves an anti-tumor role; supporting this idea, we also confirmed that CCL2 is negatively regulated by AR signaling in the preliminary data. Thus, the second aim is to characterize the AR-suppressed signaling involved in tumor promotion and the underlying mechanisms. We will analyze the anti-tumor functions of the AR mediated by its downstream proteins and microRNA (miRs) since we show that miR-1 is positively regulated by the AR and that can inhibit many other oncogenic factors in the preliminary studies. Our third goal of the proposal is to initiate a translational research by targeting inflammation signaling to prevent tumor progression. Therefore, we will develop effective approaches to delivery miR-1-based therapeutics and examine the anti-tumor effects in vivo. Furthermore, we will identify the key components in a plant extract showing anti-inflammation and anti-metastasis effects, and study the mechanisms. We will test and compare the effects of other natural products with known anti-inflammation activities.