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

目前还没有令人满意的方法来非侵入性地检测临床上的耐药癌症。对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，但许多患者由于先天性或获得性耐药而对化疗无反应。该项目的重点是使用正电子发射断层扫描（PET）成像非小细胞肺癌的耐药性。我们将靶向抗氧化反应的主要调节因子，核因子红细胞相关因子-2（Nrf 2），其在耐药NSCLC中高度表达。恶性细胞中Nrf 2的异常表达通过表达参与药物解毒和药物外排的关键蛋白质和抗氧化剂（如谷胱甘肽（GSH）、谷胱甘肽-S-转移酶（GST）和反向转运体xCT）而导致耐药性。（4S）-4-（3- [18 F]氟丙基）-L-谷氨酸盐（[18 F]FSPG）是一种通过xCT转运的放射性示踪剂，因此将用于间接成像Nrf 2。然而，直接成像Nrf 2更理想，因此该项目的第二部分重点是开发直接与Nrf 2相互作用的新型PET放射性示踪剂。将在体外评估合成Nrf 2抑制剂的Nrf 2结合和亲和力，然后进行放射性标记并在体内评估。

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.