Exploring c-Met and HER3 crosstalk by nano-proximity imaging for understanding its clinical significance in lung adenocarcinoma.

肺癌长期以来一直以难以治疗而闻名，特别是因为它经常在扩散到其他器官后才被发现。然而，医生和肺癌科学家对一种被称为“癌症生长阻滞剂”的新型靶向疗法感到非常兴奋，这种疗法可以阻断体内控制生长的天然化学物质（“生长因子”）与接收这些生长因子信号的细胞部分之间的相互作用。这种生长信号是由癌细胞不受控制地产生的，因此阻断这种信号的药物可能是阻止癌症生长的一种非常有效的方法。事实上，这些药物现在通常用于几种类型的癌症，包括一种称为“非小细胞肺癌”的肺癌。一个特别重要的例子是阻断一种主要信号受体或“受体”的药物——被称为“表皮生长因子受体”——例如吉非替尼或厄洛替尼，它们大大提高了肺癌患者的预期寿命。不幸的是，癌症往往会通过寻找其他途径，通过不同的受体来传递来自生长因子的信息，从而对这些药物产生抗药性。也就是说，如果一个受体被药物阻断，随着时间的推移，另一个受体可以开始接收到同样的信号，这意味着治疗停止了。“治疗抵抗”。我将使用一种特殊类型的显微镜，使用“FLIM”（荧光终身成像显微镜），使我们能够看到这些受体如何位于细胞中，以及它们对治疗的反应有多活跃。然后，我将使用来自不同患者的肿瘤细胞（有或没有产生耐药性）来测试一种针对不同类型受体“c-Met”的新“抑制剂”，因为有一些很好的证据表明它在肺癌信号传导中的重要性，特别是如果癌症对其他治疗有耐药性。然后将这些细胞注射到一小部分小鼠体内，这些小鼠可以接受药物治疗，以观察癌症在活体中的表现。然后，我将使用这种特殊的显微镜来检查形成的肿瘤以及这种药物在老鼠身上的效果，然后在病人的活检标本上，来预测对这种药物的反应。最重要的发现之一将是更详细地了解治疗耐药性。这也将使我们能够确定那些将从使用新药中受益的患者，这些新药可能会战胜耐药性，而不会让其他人因为不适合他们的癌症类型而受到副作用的影响。在未来，这些信息将有助于其他科学家开发预测肺癌对治疗反应的方法，从而将重点放在将从中受益最多的患者身上。这可能使药物试验更加负担得起，并可能使患者更容易获得药物试验，从而在资源稀缺的时候避免浪费。这项研究将由一名在呼吸医学方面受过高等培训的研究医生进行，他对照顾肺癌患者特别感兴趣。研究团队还将包括一名具有肺癌研究专长的资深胸科医生和一名肿瘤学教授。这项研究将主要在实验室进行，使用非常专业的显微镜研究细胞和小鼠。此外，这项研究的一个重要部分将是患者捐赠给研究的样本，包括已经手术过的肺肿瘤，以及来自腺体的材料，这些材料将为我们提供有关癌症扩散原因的独特信息。这是肺癌研究中一个令人兴奋的领域，它有机会帮助患有一种极其难以治疗的疾病的患者，这种疾病在诊断时可能使患者的预期寿命不到6个月。对于那些治疗无效、预期寿命极低的患者，这种方法可以为那些只剩下几周或几个月生命的人带来新的生命。

Lung cancer has a long-standing reputation of being difficult to treat, particularly since it is often identified after spread to other organs. However, doctors and lung cancer scientists have become very excited about a new type of targeted therapy known as a "cancer growth blocker", that blocks the interaction between natural chemicals in the body controlling growth ("growth factors") with the part of the cell that receives the signal of these growth factors. Such growth signals are produced uncontrollably by cancer cells so that drugs blocking the signal could be a highly effective way to block cancer growth. In fact, these drugs are now commonly used in a several types of cancer including a form of lung cancer called "Non-small cell lung cancer". One particularly important example are drugs that block one of the main signal receivers or "receptors" - known as the "epidermal growth factor receptor" - e.g. Gefitinb or Erlotinib, which have considerably improved the life expectancy of lung cancer sufferers.Unfortunately the cancer often becomes resistant to these drugs by finding other ways to communicate the message from the growth factors via different receptors i.e. if one receptor is blocked by drug, with time, another receptor can start receiving the same signal, which means the treatments stop working i.e. "treatment resistance". I will use a special type of microscope that uses "FLIM" (Fluorescence Lifetime Imaging Microscopy) that allows us to see how these receptors are located in the cell and how active they are in response to treatment. I will then use cells from tumours of different patients (that have or have not developed resistance) to test a new "inhibitor" against a different type of receptor "c-Met" because there is some good evidence to suggest its importance in lung cancer signalling, particularly if the cancer is resistant to other treatments. These cells can then be injected into a small number of mice that can be treated with the drugs to see how the cancer behaves in a living organism. I will then use this special microscope to examine the tumours formed and the effect of this drug in mice, and later on in biopsy specimens from patients, to predict response to the drug. One of the most important findings will be understanding treatment resistance in more detail. This will also allow us to identify patients that will benefit from the use of new drugs that may beat resistance, without subjecting others to the side effects if they are not suited to their type of cancer.In the future, such information would be useful to other scientists developing ways of predicting lung cancer responsiveness to treatment to focus the patients who will benefit most from them. This could make drug trials more affordable and potentially more accessible for patients, thus avoiding waste in a time when resources are scarce.This research will be conducted by a research doctor training at a higher level in respiratory medicine who has a particular interest in caring for patients with lung cancer. The research team will also include a senior chest physician with expertise in lung cancer research and a professor of oncology. This research will be largely based in the laboratory, studying cells and mice using very specialised microscopes. In addition, an important part of the study will be on samples that patients have donated to research including lung tumours that have been operated on but also materials coming from glands that will give us unique information about why cancer spreads.This is an exciting area in lung cancer research which has the opportunity to help patients in a disease which can be extremely difficult to treat and can leave patients with life expectancies of less than six months at diagnosis. In patients in whom the treatment has stopped working where life expectancy can be be extremely poor, this kind of approach could offer a new lease of life to those with weeks or months to live.