Imaging Metallomics - Picturing Metal Behaviour in Cancer

金属离子具有独特的化学性质，使其中一些成为人体健康的必需营养素。另一方面，如果对贩运人口活动的管制不严，则会助长疾病的发展。许多药物要么（i）在其结构中含有金属，要么（ii）通过影响我们体内的金属贩运来发挥作用。基于金属铂的药物被广泛用于治疗多种癌症，包括卵巢癌，但不幸的是，在许多患者中，肿瘤最终停止对治疗的反应并变得“铂耐药”，使患者的治疗选择减少，生存率降低。从对细胞和患者活检的研究中发现，铂耐药癌症倾向于减少铂药物的摄取。虽然铂类药物进入肿瘤的确切机制尚不完全清楚，但一些研究表明，这些药物可以使用与铜相同的“门道”进入细胞，铜是一种对我们的健康至关重要的金属。因此，铂类药物在卵巢癌中的积累，以及它们对这些药物的潜在反应能力，可能与肿瘤积累铜的能力有关。在这个项目中，我将研究卵巢癌对铂类药物的耐药性与其积累这些药物和铜的能力之间的关系。我还将研究去除铜，从而使肿瘤对这种必需营养素更加“饥饿”，是否也会诱使它服用更多的铂类药物，从而可能逆转铂类药物的耐药性。为了研究所有这些在体内发生的过程，我将用放射性标签标记铂类药物和铜，这样我们就可以用扫描仪在活体内实时跟踪它们。该项目不仅将提高我们对卵巢癌为什么会对铂类药物产生耐药性的理解，而且还将开发基于成像的工具来检查患者的肿瘤是否对铂类药物产生耐药性，以便患者可以接受不同的治疗。最后，对逆转铂类耐药策略的研究将有助于增加可以从铂类药物中获益的患者数量。

Metal ions have unique chemical properties that make some of them essential nutrients for human health. On the other hand, if their trafficking is dysregulated this can contribute to development of disease. Many drugs either (i) contain a metal in their structure or (ii) exert their action by influencing metal trafficking in our body. Drugs based on the metal platinum are widely used in the treatment of several cancers, including ovarian cancer, but unfortunately in many patients the tumour eventually stops responding to treatment and becomes 'platinum resistant', leaving patients with fewer therapeutic options and poorer survival rate. It has been found, from studies in cells and patient biopsies, that platinum resistant cancer tends to take up less of the platinum drug. While the exact mechanism through which platinum drugs enter the tumours is not fully known, some studies showed that these drugs could use the same 'doorway' into the cell used by copper, a metal essential for our health. Therefore, accumulation of platinum drugs in ovarian cancer, and potentially their ability to respond to these drugs, could be linked to the tumour's ability to accumulate copper. In this project, I will study the relationship between resistance to platinum drugs in ovarian cancer and its ability to accumulate these drugs and copper. I will also investigate whether removing copper, thus making the tumour more 'hungry' for this essential nutrient, will also trick it into taking up more platinum drugs, potentially reversing platinum resistance. To study all of this while it's happening inside the body, I will label both the platinum drugs and copper with a radioactive tag so that we can track them inside a living organism in real-time images using a scanner. This project will not only improve our understanding of why ovarian cancer becomes resistant to platinum drugs but will also enable the development of imaging-based tools to check if a patient's tumour is resistant to platinum drugs, so that the patient can be moved to different treatments. Finally, research into strategies to reverse platinum resistance will help increasing the number of patients that can benefit from platinum drugs.