Platinum drugs in the tumor microenvironment

Research context. Colorectal cancer (CRC) is one of the most common cancer types worldwide and remains a leading cause of cancer-related deaths. Despite the widespread use of platinum-based chemotherapy agents (such as oxaliplatin) in CRC treatment, their therapeutic efficacy is limited by poor drug accumulation in tumor tissues and severe systemic side effects. To overcome these challenges, we developed a novel oxaliplatin-releasing platinum(IV) prodrug (KP2156), which uses albumin as carrier for tumor-specific drug delivery. However, although albumin-based cancer targeting strategies are clinically promising, still many aspects are unexplored. Noteworthy, solid tumors are complex tissues containing also many other cell types. Aim. Although these cell types show high cellular albumin uptake, their role in the prodrug activation and anticancer response is widely unknown. Consequently, the aim of this project is to investigate, how the albumin-mediated platinum prodrug KP2156 compared to free oxaliplatin affects tumor vs. non-malignant cells (e.g. immune cells and cancer-associated fibroblasts). Methods. To this end, colon cancer samples collected from drug-treated mice will be 1) evaluated by single-cell RNA sequencing (scRNA-seq) and bioinformatics analysis of the gained transcriptional profiles and 2) mapped by multiplexed imaging using laser ablation inductively coupled plasma time- of-flight mass spectrometry (LA-ICP-TOFMS). Innovation. The collected data will allow to understand the role of non-malignant cells in the activity of albumin-targeted therapy and help to better select patients for future clinical trials. Primary researchers involved. The project will be performed by a unique and highly interdisciplinary team consisting of experts in preclinical drug development (Petra Heffeter, Center of Cancer Research, Medical University of Vienna), single-cell RNA-sequencing (Bernhard Englinger, Department of Urology, Medical University of Vienna) and spatial tissue analysis using LA-ICP-TOFMS (Gunda Koellensperger, Institute of Analytical Chemistry, University of Vienna)