Transcriptional reprogramming of lactate metabolism in prostate cancer: druggable vulnerabilities for therapeutic and diagnostic applications.

The goal of this study is to shed light on the molecular processes that control MCT1 and lactate metabolism in prostate cancer (PCa) and to analyze their roles in promoting metastasis. We aim to discover new targets that are relevant for diagnosis and treatment, while also creating new compounds that can target MCT1 for possible use in both therapy and diagnostics. The Study will combine molecular, genetic, cellular, and medicinal chemistry methodologies. The first work package is dedicated to the molecular characterization of the NF-Y/MCT1/lactate axis in the aggressiveness of PCa. We demonstrated that the expression of the NF-YA subunit correlates with clinical outcomes, influencing cancer traits. NF-Y governs cell metabolism through the expression of genes implicated in cancer metabolism, such as MCT1. The project will employ loss and gain of function methods to manipulate NF-YA expression in different PCa cell lines to investigate its influence on lactate metabolism and metastatic capacity. These experiments will focus on evaluating metabolic alterations and changes in gene expression in response to diverse nutritional settings, that reflect the complexity of the tumor microenvironment (TME). In the second work package, we will identify novel biomarkers for PCa using advanced proteomics. Current biomarkers like Gleason score and PSA are insufficient for distinguishing aggressive tumors. We will use proteomic technologies to find new biomarkers linked to NF-YA expression under different glucose and lactate availability conditions. Their clinical significance will be evaluated through bioinformatics and tissue analysis to improve patients’ stratification for proper therapeutic interventions. The third work package focuses on creating innovative MCT1 inhibitors for both diagnostic and therapeutic applications. Targeting MCT1 could be an effective approach against both glycolytic and oxidative cancer cells due to their metabolic symbiosis. We will develop new MCT1 inhibitors through design and synthesis. These inhibitors will be tested in vitro to determine their effectiveness. Additionally, the project aims to investigate the potential of using bifunctional chelators for radiolabeling, with the goal of developing theragnostic agents. Collaboration with experts in macrocyles and radiochemistry will aid in optimizing these inhibitors for clinical applications. This project will lead to improved patient outcomes and progress in prostate cancer research. The results will be disseminated to the general public and academia via social media platforms, public events, and international conferences, to advance scientific understanding and promote enthusiasm for STEM disciplines, with a special focus on engaging younger generations. In addition, the findings will be disseminated through publication in peer-reviewed scientific publications, which will enhance their visibility and facilitate scientific collaboration.