Project Details
Projekt
Understanding the relevance of RAI2 activity in emerging therapy-resistance of castration-resistant prostate cancer
Subject Area
Reproductive Medicine, Urology
Hematology, Oncology
Hematology, Oncology
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 439618222
Prostate cancer is a hormone-driven disease, and its tumor cell growth is highly dependent on androgen receptor (AR) signaling. Therefore, targeted therapy against androgen synthesis or AR activity is widely used and continuously improved. In unfortunate cases, under the constant pressure of androgen deprivation therapy, advanced prostate cancer can develop resistance to the latest generation of AR inhibitors and transdifferentiate into even more aggressive, treatment-resistant subtypes. In this context, increased expression, and activity of the key epigenetic regulator Enhancer of Zeste Homolog 2 (EZH2) as a catalytic component of the Polycomb 2 Repressor Complex has been shown to enable phenotypic plasticity and therapy resistance. During the first funding period, we showed for the first time that Retinoic Acid Induced 2 (RAI2) gene and protein expression is associated with androgen receptor activity and epithelial differentiation in primary tumors and circulating tumor cells. We also confirmed that the RAI2 protein functions as a transcriptional co-regulator of AR signaling. In addition, we discovered that in addition to its function as an AR co-regulator, RAI2 suppresses phenotypic plasticity and counteracts the activity of EZH2. In the next funding period, we plan to continue our efforts to better understand the biological relevance of RAI2 activity in the progression of advanced prostate cancer and the development of therapeutic resistance. In addition, we intend to continue our efforts to develop and test liquid biopsy assays for the early detection of prostate cancer patients who no longer benefit from anti-hormonal therapy. We will address the following questions: - Is RAI2 required to establish the castration-resistant prostate cancer phenotype? - How does loss of RAI2 in advanced prostate cancer cells contribute to androgen receptor signaling and induction of phenotypic plasticity at the molecular level? - Do tumor cells and tumor cell products in the circulation reflect the development of phenotypic plasticity and therapy resistance?
DFG Programme
Research Grants
