Approximately 4 million cats develop cancer every year and about one-third of cats die from cancer. For cats with advanced solid tumors (e.g. carcinomas and sarcomas), systemic chemotherapy is often the only treatment option. These types of cancer cells, regardless of underlying tumor histology, are relatively chemoresistant. Response rates are low, and duration of response is short in cats that do respond. Furthermore, biomarkers or phenotypic predictors of drug response are lacking. This means there is no way to identify which cats will respond to treatment. To help a few, you have to treat many. In addition to novel treatment strategies, we need mechanisms to precisely identify which cats will benefit from which treatments. The broad objectives of our research are to identify treatment strategies that overcome chemoresistance in feline solid tumors and to validate metasurface-enhanced infrared reflection spectroscopy (MEIRS) as a phenotypic sensor of chemosensitization. This technique is label-free and detects biochemical changes and cytoskeleton reorganization close to the cellular membrane. The aim of this proposal is to test the hypothesis that feline cancer cells sensitized to doxorubicin by the ionophore salinomycin have a repeatable spectroscopic signature independent of tumor histomorphology. To test this hypothesis, we will use MEIRS to determine the spectroscopic signature associated with salinomycin-mediated reversal of doxorubicin resistance in feline carcinoma and sarcoma cells (Aim 1.1). We will also determine the spectroscopic signature associated with salinomycin exposure in carcinoma and sarcoma tissue samples using a mouse xenograft model (Aim 1.2). The combination of our in vitro and ex vivo experiments is necessary to establish that the MEIRS technique can be used to assess chemosensitization in both clinical cytology samples (i.e. obtained via fine needle aspirate) and clinical histology samples (i.e. obtained via biopsy).