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

通过纳米邻近成像探索 c-Met 和 HER3 串扰，以了解其在肺腺癌中的临床意义。

基本信息

批准号：
MR/L001772/1
负责人：
Richard Lee
金额：
$ 19.46万
依托单位：
King's College London
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2013
资助国家：
英国
起止时间：
2013 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FL001772%2F1
关键词：
Exploring Met HER3 crosstalk nano

项目摘要

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.

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不受控制地产生的，因此阻断信号的药物可能是阻止癌症生长的高效方法。事实上，这些药物现在常用于治疗多种类型的癌症，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主要信号接收器或“受体”之一（称为“表皮生长因子受体”）的药物。吉非替尼或厄洛替尼，大大提高了肺癌患者的预期寿命。不幸的是，癌症常常通过寻找其他方式通过不同的受体传达来自生长因子的信息而对这些药物产生耐药性，即如果一种受体被药物阻断，随着时间的推移，另一种受体可以开始接收相同的信号，这意味着治疗停止起作用，即“治疗抵抗”。我将使用一种特殊类型的显微镜，该显微镜使用“FLIM”（荧光寿命成像显微镜），使我们能够看到这些受体在细胞中的位置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（已产生或未产生耐药性）的肿瘤细胞来测试针对不同类型受体“c-Met”的新“抑制剂”，因为有一些充分的证据表明其在肺癌信号传导中的重要性，特别是当癌症对其他治疗有耐药性时。然后可以将这些细胞注射到少量接受药物治疗的小鼠体内，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小鼠中形成的肿瘤和这种药物的效果，然后检查患者的活检标本，以预测对该药物的反应。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出那些可以从使用可能战胜耐药性的新药中受益的患者，而不会让其他人在不适合其癌症类型的情况下遭受副作用。将来，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，以关注将从中受益最大的患者。这可以使药物试验变得更加经济实惠，并且可能更容易为患者所接受，从而避免资源稀缺时期的浪费。这项研究将由一位接受过呼吸医学更高水平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在肺癌研究方面具有专业知识的高级胸科医师和一名肿瘤学教授。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，该研究的一个重要部分将是患者捐赠给研究的样本，包括已经做过手术的肺部肿瘤，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，并且可能使患者在诊断时的预期寿命不足六个月。对于治疗已经停止、预期寿命极短的患者，这种方法可以为那些只剩下几周或几个月的生命的人提供新的生命。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

MET-EGFR dimerization in lung adenocarcinoma is dependent on EGFR mtations and altered by MET kinase inhibition.

DOI：
10.1371/journal.pone.0170798
发表时间：
2017
期刊：
PloS one
影响因子：
3.7
作者：
Ortiz-Zapater E;Lee RW;Owen W;Weitsman G;Fruhwirth G;Dunn RG;Neat MJ;McCaughan F;Parker P;Ng T;Santis G
通讯作者：
Santis G

Gene expression profiling of endobronchial ultrasound (EBUS)-derived cytological fine needle aspirates from hilar and mediastinal lymph nodes in non-small cell lung cancer.

非小细胞肺癌肺门和纵隔淋巴结支气管内超声（EBUS）衍生细胞学细针抽吸物的基因表达谱。