A new study, published in European Urology Oncology, describes the in vitro and in vivo activity of EC-8042, a novel anticancer compound that interferes with transcriptional reprogramming and expansion of cancer stem cells in preclinical models of ERG positive prostate cancer. The study was carried out in collaboration with Entrechem (Oviedo, Spain).
Transcriptional reprogramming and inhibition of tumor-propagating stem-like cells by EC-8042 in ERG-positive prostate cancer
Dheeraj Shinde, Domenico Albino, Marita Zoma, Azzurra Mutti, Sarah N. Mapelli, Gianluca Civenni, Aleksandra Kokanovic, Jessica Merulla, Jhudit Perez-Escuredo, Paula Costales, Francisco Morìs, Carlo V. Catapano, Carbone G.M.
Background: The TMPRSS2-ERG gene fusion is the most frequent genetic rearrangement in prostate cancers and results in broad transcriptional reprogramming and major phenotypic changes. Interaction and cooperation of ERG and Sp1 may be instrumental for sustaining the tumorigenic and metastatic phenotype and represent a potential vulnerability in ERG fusion positive tumors.
Objective: To test the activity of EC-8042, a compound able to block Sp1, in cellular and mouse models of ERG positive prostate cancer.
Design, setting, and participants: We evaluated the activity of EC-8042 in cell cultures and ERG/PTEN transgenic/knockout mice that provide reliable models for testing novel therapeutics in this specific disease context. Using a new protocol to generate tumor-spheroids from ERG/PTEN mice, we also examined the effects of EC-8042 on tumor-propagating stem-like cancer cells endowed of high self-renewal and tumorigenic capability.
Outcome measurements and statistical analysis: Efficacy of EC-8042 was determined by measuring proliferative capacity and target gene expression in cell cultures, invasive and metastatic capability in CAM assays, and tumor development in mice. Statistical significance between experimental groups was determined by Student’s t-test.
Results and limitations: EC-8042 blocked transcription of ERG-regulated genes and reverted the invasive and metastatic phenotype of VCaP cells. EC-8042 blocked the expansion of stem-like tumor cells in tumor-spheroids from VCaP and mouse-derived tumors. In ERG/PTEN mice, systemic treatment with EC-8042 inhibited ERG-regulated gene transcription, tumor progression and tumor-propagating stem-like tumor cells.
Conclusions: Our data support clinical testing of EC-8042 for the treatment of ERG-positive prostate cancer in a precision medicine-based approach.
Patient summary: In this study, EC8042, a novel compound with favorable pharmacological and toxicological profile, exhibited relevant activity in cell cultures and in vivo in a GEM model that closely recapitulated the features of clinically aggressive ERG-positive prostate cancers. Our data encourage further evaluation of EC-8042 in clinical trials.