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，特别是因为它通常是在扩散到其他器官后才被发现的。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，这种疗法可以阻止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无法控制地产生的，因此阻止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，这些药物现在普遍用于治疗几种癌症，包括一种被称为“非小细胞肺癌”的肺癌。一个特别重要的例子是阻断主要信号接收器或“受体”之一--被称为“表皮生长因子受体”--的药物，例如格非替尼或厄洛替尼，它们极大地延长了肺癌患者的预期寿命。不幸的是，癌症往往会通过其他途径通过不同的受体传递生长因子的信息，从而对这些药物产生抗药性，即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相同的信号，这意味着治疗方法停止工作，即“治疗抵抗”。我将使用一种特殊类型的显微镜，它使用Flim(荧光寿命成像显微镜)，使我们能够看到这些受体如何在细胞中定位，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(已经或尚未产生耐药性)的肿瘤细胞来测试一种新的“抑制剂”，以对抗一种不同类型的受体“c-Met”，因为有一些很好的证据表明，它在肺癌信号传递中具有重要作用，特别是在癌症对其他治疗具有耐药性的情况下。然后，这些细胞可以被注射到少数可以用药物治疗的小鼠体内，以观察癌症在活的有机体中的表现。然后，我将使用这个特殊的显微镜来检查在小鼠身上形成的肿瘤和这种药物的效果，然后在患者的活检样本中检查，以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。这也将使我们能够识别那些将从使用可能克服耐药性的新药中受益的患者，而不会让其他人在不适合自己的癌症类型的情况下遭受副作用。未来，这些信息将对其他科学家有用，他们将开发预测肺癌对治疗的反应性的方法，以关注将从治疗中受益最大的患者。这可能会使患者更容易负担得起药物试验，从而在资源稀缺的时候避免浪费。这项研究将由一名受过更高水平呼吸系统医学培训的研究医生进行，他对护理肺癌患者特别感兴趣。研究团队还将包括一名在肺癌研究方面具有专业知识的资深胸科医生和一名肿瘤学教授。这项研究将主要以实验室为基础，使用非常专业的显微镜研究细胞和老鼠。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，包括接受过手术的肺癌，以及来自腺体的材料，这些材料将为我们提供关于癌症扩散的独特信息。这是肺癌研究中一个令人兴奋的领域，有机会帮助患有这种疾病的患者，这种疾病可能非常难以治疗，患者确诊时的预期寿命可能不到6个月。在预期寿命可能非常低的患者中，治疗已经停止奏效，这种方法可能会为那些还能活几周或几个月的人提供新的生命。

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.