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

目前临床上还没有令人满意的非侵入性检测耐药癌症的方法。对支持耐药性的分子过程进行成像可以在疾病的早期阶段提供挽救生命的诊断信息。非小细胞肺癌(NSCLC)是最致命的癌症类型之一，但由于先天或后天耐药，许多患者对化疗没有反应。本项目的重点是利用正电子发射断层扫描(PET)对非小细胞肺癌的耐药性进行成像。我们将针对抗氧化反应的主要调节因子-核因子红系相关因子-2(Nrf2)，它在耐药非小细胞肺癌中高度表达。肿瘤细胞中NRF2的异常表达通过参与药物解毒的关键蛋白和抗氧化剂的表达，以及药物外排，如谷胱甘肽、谷胱甘肽S转移酶和反向转运蛋白XCT的表达，参与了药物耐药的发生。(4S)-4-(3-[18F]氟丙基)-L-谷氨酸([18F]FSPG)是一种通过XCT转运的放射性示踪剂，因此将被用于间接成像NRF2。然而，直接成像NRF2更理想，因此本项目的第二部分专注于开发与NRF2直接作用的新型PET放射性示踪剂。人工合成的Nrf2抑制剂将在体外评估Nrf2的结合和亲和力，然后进行放射性标记和体内评估。

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.