PET imaging diagnostics of mitochondrial homeostasis in precision cancer medicine

Abstract

Mitochondrial homeostasis serves as a ‘gate-keeper’ for a cell’s viability and plays key regulatory roles in apoptotic cell death, metabolism, reactive oxygen species accumulation/defense, and various biosynthetic pathways. Given the complex intricacies of these processes in cancer, molecular imaging agents that can illuminate the interplay of mitochondrial pathway reprogramming could have implications towards improving cancer detection, drug discovery, assessing treatment response, and disease staging. As such, there is a clinical need to develop novel imaging agents for Positron Emission Tomography (PET) which target unique biomarkers involved in cancer development. This work reports the discovery and characterization of a novel PET imaging probe, [18F]FB-VAD-FMK, for in vivo caspase activity detection. These studies revealed this peptide class to be a promising scaffold for molecular imaging agent development for cell death detection. In analogous PET imaging studies of cancer cell nutrient uptake and metabolism, glutamine-derived PET was explored as a measure of molecular response to targeted therapy as well as a means for reporting mutant gene expression in genetically engineered mice. Towards exploring novel biomarkers in early stage disease, translocator protein (TSPO) expression was discovered to be a potential marker of early gastrointestinal (GI) neoplasia and precursor lesions. Conclusively, these findings provide a basis for ultimately translating novel, non-invasive imaging metrics into clinical practice.