Biomarkers of cancer drug-responses

The pre-clinical anticancer agent PR-104A is a DNA alkylating agent that requires metabolic activation. Levels of PR-104A-derived DNA adducts have been shown to be dependent on enzyme activity and correlate with in vitro responsiveness of cancer cells. The goal of this project is to identify biochemical characteristics of PR-104A-responsiveness like protein levels of drug-activating enzymes and drug-specific DNA adducts as candidate biomarkers for precision therapy. We are establishing a model of how cellular proteins affect drug-specific DNA alkylation patterns and elucidating the relationship between drug efficacy and PR104A-DNA adduct profiles in various biological models such as cancer patient-derived xenografts using tailored bioanalytical approaches including stable isotope labeled LC-MS methods. The proposed research has the potential to impact cancer therapy through the development of an innovative combination of diagnostic and therapeutic strategies and also to shed light on fundamental concepts important for advancing precision medicine on the basis of understanding molecular processes.