ABSTRACT Given the clinical importance of minimal residual disease in Her2 positive (Her2+) breast cancer, understanding how these residual tumor cells rewire their metabolic pathways is critical for developing strategies to eliminate residual disease and/or prevent the subsequent re-activation of residual tumors into recurrence. Currently, there are no techniques available to provide a systems level approach to image the major axes of metabolism at a spatial resolution that can elucidate the modulation of cancer residual cell metabolism in vivo. Our technological goal is to create an innovative platform to image tumor metabolism at a spatial resolution that allows for visualization of primary tumors, residual disease, and recurrence following neoadjuvant therapy in order to facilitate understanding of tumor biology and function, assessment of recurrence risk, and design of therapies that can mitigate residual disease and recurrence altogether. Our technological approach fills an important gap that exists between in vitro studies on single cells (Seahorse Extracellular Flux Assay) and whole-body imaging (fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) imaging) and is complementary to metabolomics and immunohistochemistry with endpoints measuring the major axes of metabolism. The specific goals of this proposal are to validate use of a fatty acid uptake probe to image fatty acid oxidation in vivo and integrate this endpoint into our previously validated methods of near simultaneous imaging of glucose uptake to measure glycolysis and mitochondrial membrane potential to measure mitochondrial activity. This will allow for orthotopic, in vivo imaging of tumor metabolism (Aim 1). From here, we will apply this integrated technology to measure key axes of metabolism during tumor progression, regression, residual disease, and recurrence following typical therapy regimes in vivo using a mammary window chamber and GEM model derived cells (Aim 2).

NARRATIVE The goal of our proposed work is to establish a novel platform to image tumor metabolism, vascular function and architecture at high resolution to address questions in the field of breast HER2+ cancer residual disease and recurrence. Our system will provide insight into the changes in cancer cell metabolism that underpin therapy evasion and tumor recurrence, in order to facilitate understanding of tumor biology and function, assessment of recurrence risk, and design of therapies that can mitigate residual disease and recurrence altogether.