Targeting Methylated ERG with an Intracellular Minibody in Prostate Cancer
About 50% of prostate cancers carry the TMPRR2:ERG gene rearrangement with overexpression of the transcription factor ERG. Our research has shown that methylation of ERG at lysine 362 by the protein methyltransferase EZH2 enhances ERG oncogenic activity, promoting tumor growth and malignancy. These findings underscore the potential of targeting methylated ERG (mERG) as a novel therapeutic strategy in ERG gene fusion-positive prostate cancer.To this end, we developed a monoclonal antibody specifically recognizing ERG methylated form. For intracellular delivery, we reformatted the antibody into a single-chain variable fragment (anti-mERG minibody) and employed a DNA plasmid system for its intracellular expression. Our studies show that the anti-mERG minibody is expressed in cells and suppresses mERG activity in preclinical models. Preliminary results following intravenous administration of this DNA plasmid with polymeric nanoparticles in mice bearing tumor xenograft showed significant tumor growth inhibition without detectable toxicity.The goal of this project is to optimize the delivery system for our anti-mERG minibody and validate its therapeutic efficacy. We will investigate the use of Nanoplasmid DNA and mRNA-based technologies to enhance delivery efficiency and safety in both in vitro and in vivo models. These experiments will lay the groundwork for translating our anti-mERG minibody into a novel treatment for prostate cancer. Beyond its potential to improve patient outcomes, this innovative approach could have a considerable economic impact, given the anticipated growth of the prostate cancer treatment market. We believe that our proposed preclinical package will pave the way for further development and commercialization of this groundbreaking therapy.
This project is funded by Innosuisse.