Imaging Metallomics - Picturing Metal Behaviour in Cancer

金属离子具有独特的化学性质，使其中一些对人类健康至关重要的营养物质。另一方面，如果它们的贩运不受管制，这可能会导致疾病的发展。许多药物要么(I)在其结构中含有金属，要么(Ii)通过影响人体内的金属交易而发挥作用。基于金属铂的药物被广泛用于包括卵巢癌在内的几种癌症的治疗，但不幸的是，在许多患者中，肿瘤最终对治疗无效，并对铂产生抗药性，导致患者的治疗选择更少，存活率更低。从细胞研究和患者活检中发现，对铂耐药的癌症往往会较少地使用铂类药物。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，这些药物可以使用铜进入细胞的同一“大门”，铜是我们健康必不可少的一种金属。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。我还将研究去除铜是否也会诱使肿瘤吸收更多的铂类药物，从而有可能逆转对铂的耐药性。为了研究在体内发生的所有这些，我将用放射性标签标记铂药物和铜，这样我们就可以使用扫描仪在活体内实时跟踪它们。这个项目不仅将提高我们对卵巢癌对铂类药物产生抗药性的理解，还将使基于成像的工具的开发成为可能，以检查患者的肿瘤是否对铂类药物具有抗药性，从而使患者能够转移到不同的治疗方法。最后，研究逆转铂耐药性的策略将有助于增加可以从铂类药物中受益的患者数量。

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.