Exploiting the vulnerabilities of drug-resistant lung cancer with theranostics

耐药是目前临床肿瘤学面临的最大问题之一。尽管新的抗癌疗法发生了革命，如检查点抑制剂和质子束疗法，但由于对现有治疗方法的后天或先天抵抗，往往观察不到持久的反应[1]。通过这个项目，我们将开发一个创新的临床前研究计划，以非侵入性地检测和治疗耐药肺癌。迫切需要为这些患者开发新的治疗方法；肺癌是全球最常见的癌症死亡原因，每年约有160万人死亡，十年生存率仅为5%[2]。肿瘤氧化还原微环境的松弛导致治疗抵抗生化抗氧化机制在获得性耐药的形成中起着关键作用[3]。肿瘤抗氧化反应的中心是XCT，一种氨基酸转运蛋白，在耐药肺癌中上调数倍。XCT为谷胱甘肽的生物合成提供限速前体，谷胱甘肽是人体内含量最丰富的抗氧化剂。我们已经建立了医学成像工具来评估活体受试者的XCT活动[4，5]。重要的是，利用肺癌的基因工程小鼠模型和患者衍生的肿瘤模型，我们使用这些工具对耐药癌症中XCT的过度表达进行了成像。我们将使用一种称为放射免疫疗法的治疗平台来探索导致现有治疗失败的机制。放射免疫治疗是一种创新的方法，通过抗体靶向将发射α或β粒子的放射性核素输送到耐药肿瘤中，而对正常健康细胞的影响最小。在这里，我们将使用一种高度特异的人类嵌合单抗作为我们的XCT靶向试剂(与AgilVax公司合作)，并用放射性核素标记XCT。这种放射性核素通过发射低(例如贝塔)或高(例如阿尔法)线性能量转移粒子直接向肿瘤提供辐射有效载荷，这些粒子会导致DNA单链和双链断裂，从而导致细胞死亡。此外，通过将治疗性放射性同位素转换为用于医学成像的放射性同位素，我们可以在治疗前选择抗原高表达的肿瘤，并在治疗过程中和之后监测治疗效果。我们将共同开发用于肺癌精确治疗的新型XCT疗法。假设：XCT治疗药物将在耐药肿瘤中高水平积聚，引发强大的抗肿瘤反应。我们在WP1中设计和合成的抗癌化合物将用于在活体时间进程PET成像中有效显示耐药肺癌。随后，我们的XCT靶向治疗药物携带治疗性Lu-177同位素将被用于选择性地杀死耐药肺癌，因为它们的XCT表达增加。发射β辐射的Lu-177放射治疗将向肿瘤和肿瘤微环境提供辐射有效载荷，导致ROS产生，DNA损伤，最终细胞死亡。能够恢复细胞氧化还原动态平衡的幸存癌细胞很可能采用进一步提高XCT表达的机制。XCT的上调随后将增加细胞内化的治疗量，创建一个正反馈循环，将我们的治疗有效载荷提供给那些对治疗具有耐药性的肿瘤。这些研究将使用肺癌的原位模型来测量治疗药物在肿瘤中的积累，并评估它们对耐药肺癌的治疗效果。重要的是，初步工作表明，小分子XCT放射性示踪剂在耐药肺癌的异种移植模型中积聚水平较高，而在所有其他健康器官中的积聚较低(治疗指数大)。

Therapy resistance is one of the biggest problems currently facing clinical oncology. Despite a revolution in new anti-cancer therapies, such as check-point inhibitors and proton beam therapy, durable responses are often not observed due to acquired or innate resistance to existing treatments [1]. Through this project, we will develop an innovative preclinical programme of research to non-invasively detect and treat drug resistant lung cancer. There is an urgent need to develop new therapies for these patients; lung cancer is the most common cause of cancer death world-wide with ~1.6 million deaths/year and a ten-year survival rate of just 5% [2]. Deregulation of the tumour redox microenvironment drives therapy resistanceBiochemical antioxidant mechanisms play a critical role in development of acquired drug-resistance [3]. Central to the tumour antioxidant response is xCT, an amino acid transporter which is upregulated many-fold in drug-resistant lung cancer. xCT provides the rate-limiting precursors for glutathione biosynthesis, which is the body's most abundant antioxidant. We have built medical imaging tools to evaluate xCT activity in living subjects [4,5]. Importantly, using genetically engineered mouse models of lung cancer and in patient-derived tumour models we have used these tools to image xCT over-expression in drug-resistant cancer.We will exploit the very mechanisms that cause existing treatments to fail using a therapeutic platform known as radioimmunotherapy. Radioimmunotherapy is an innovative approach, where an alpha or beta particle-emitting radionuclide is deliveredto the therapy-resistant tumours through antibody targeting, with minimal effect on normal healthy cells. Here, we will target xCT using a highly-specific human chimeric monoclonal antibody as our xCT-targeting agent (in collaboration with AgilVax, Inc.),tagged with a radionuclide. This radionuclide provides a radiation payload directly to the tumour through the emission of either low (e.g. beta) or high (e.g. alpha) linear energy transfer particles which cause single and double DNA strand breaks,leadingto cell death. Moreover, by switching the therapeutic radioisotope for one used in medical imaging, we can select tumours with high antigen expression prior to therapy and monitor therapeutic efficacy during and after the course of treatment.Together, we will develop novel xCT therapies for the precision treatment of lung cancer.Hypothesis: xCT theranosticswill accumulate in drug-resistant tumours at high levels, eliciting a potent anti-tumour response. Our theranostic compounds designed and synthesised in WP1 will be used for the effective visualisation of drug resistant lungcancer in vivousing time course PET imaging. Subsequently, our xCT-targeting theranostics bearing the therapeutic Lu-177isotope will be used to selectively kill drug-resistant lung cancer due to their elevated expression of xCT. The beta-emitting Lu-177radiotherapeutic will delivera radiation payload to the tumour and the tumour microenvironment, resulting in ROS production, DNA damage, and ultimately cell death. Surviving cancer cells able to restore cellular redox homeostasis are likely to employ mechanisms that further elevate xCT expression. Upregulation of xCT will subsequently increase the amount therapeutic internalised by the cell, creating a positive feedback loop, delivering higher payloads of our theranostic to those tumours that are resistant to therapy. These studies will employ orthotopic models of lung cancer to measure accumulation of the theranostics at the tumour and to evaluate their efficacy for the treatment of drug resistant lung cancer. Importantly, preliminary work has shown that small molecule xCT radiotracersaccumulates in a xenograft model of drug resistant lung cancer at high levels, with low accumulation observed in all other healthy organs (large therapeutic index)