Imaging drug resistance in cancer to predict response to therapy using a PET radiotracer targeting Nrf2, a key regulator of the tumour antioxidant res

There are currently no satisfactory ways to non-invasively detect drug-resistant cancers in the clinic. Imaging the molecular processes underpinning drug resistance could provide life-saving diagnostic information during early stages of the disease. Non-small cell lung cancer (NSCLC) is one of the most lethal types of cancer, yet many patients don't respond to chemotherapy due to innate or acquired resistance. This project focuses on using positron emission tomography (PET) to image drug resistance in NSCLC. We will target the master regulator of the antioxidant response, nuclear factor erythroid-2 related factor-2 (Nrf2), which is highly expressed in drug-resistant NSCLC. Aberrant expression of Nrf2 in malignant cells contributes to drug resistance through the expression of key proteins and antioxidants involved in drug detoxification, and drug efflux, such as glutathione (GSH), glutathione-S-transferase (GST), and antiporter xCT. (4S)-4-(3- [18F]fluoropropyl)-L-glutamate ([18F]FSPG) is a radiotracer that is transported through xCT, and thus will be used to indirectly image Nrf2. However, it is more ideal to directly image Nrf2, hence the second part of this project focuses on developing novel PET radiotracers which directly interact with Nrf2. Synthetic Nrf2 inhibitors will be assessed in vitro for Nrf2 binding and affinity, then radiolabelled and assessed in vivo.