The role of miR-31 in regulating response of colorectal cancer to EGFR inhibition - relationship to the detriment observed in the New EPOC study

肠癌是英国癌症死亡的第二大常见原因。死亡通常是由于扩散到身体其他部位，其中肝脏是最常见的部位。大约四分之一已经扩散到肝脏的肠癌患者能够通过手术切除癌细胞。其中大多数人同时接受化疗以减少癌症复发的可能性。在过去的十年里，人们对靶向癌症治疗的使用产生了兴趣，包括西妥昔单抗，这是一种生长因子阻滞剂。目前，NICE推荐这种治疗方法用于已经扩散到肝脏而不适合手术的肠癌患者，估计每位患者的额外费用为17,000英镑。新的EPOC试验是为了观察可手术肠癌患者是否也能从这种治疗中受益。该研究对肝手术前后患者进行常规化疗，有西妥昔单抗或无西妥昔单抗。其目的是观察这种疗法是否会降低癌症恶化或术后复发的几率。不幸的是，该试验产生了一个意想不到的结果，即在接受西妥昔单抗的组中，患者的癌症复发得更快。我们必须进行进一步的研究，以了解发生这种情况的原因。在同意参加试验的同时，患者也被要求同意将他们的组织用于未来的研究。这些包括他们原来肠癌的多余的福尔马林固定样本和他们肝脏手术的样本。这个组织现在形成了一个重要的资源，我们可以进行实验室研究，试图解释这个试验结果。microrna是最近发现的一种遗传物质。它们在健康组织中表达，但在癌症中被破坏。我们的初步数据显示，在新的EPOC研究中，肠癌患者表达的特定微RNA miR-31的水平可能与他们对西妥昔单抗治疗的反应有关。我的项目目的是研究这一观察结果背后的机制，即miR-31在肠癌对生长因子抑制剂西妥昔单抗的反应中的作用。我们的初步工作肯定表明它可能起着重要的作用，但目前我们还不确切地知道它控制着哪些基因。我们将探索miR-31影响肠癌进展的机制，使用经过试验和测试的实验室技术，使我们能够量化癌症侵袭和转移的发展。我们还将使用小鼠模型来复制New EPOC研究中使用的治疗方法，以分析是否是一种特定的治疗组合，例如肝脏手术结合生长因子抑制剂，是有害的。该项目对未来肠癌患者的治疗具有重要意义。目前限制西妥昔单抗用于肿瘤中没有KRAS突变的患者，包括New EPOC在内的许多研究已证明不足以预测获益。确定miR-31在调节肠癌对生长因子阻滞剂反应中的功能作用，将有助于我们了解哪些患者将从这些治疗中受益，并有助于合理选择患者使用靶向药物。这一点，连同在其他试验中miR-31作为反应预测因子的验证，可能允许开发一种测试，以便在未来更好地选择患者，从而避免那些不可能从相关毒性和失去接受其他治疗机会中获益的患者。从长远来看，它可能为肠癌开辟新的治疗机会，并且考虑到这种靶向治疗的巨大成本，也提供了健康经济优势。

Bowel cancer is the second most common cause of cancer death in the UK. Death usually results from spread to other parts of the body, of which the liver is the commonest site. Approximately one quarter of patients with bowel cancer that has spread to the liver are able to have an operation to remove the cancer. Of those the majority are treated with chemotherapy as well to try and reduce the likelihood of the cancer coming back. Over the last decade there has been interest in the use of targeted cancer therapies including cetuximab which is a growth factor blocker. This treatment is currently recommended by NICE for people with bowel cancer that has spread to the liver that is not suitable for surgery, at an estimated additional cost of £17,000 per patient. The New EPOC trial was undertaken to see if people with operable bowel cancer that has spread to the liver would also benefit from this treatment. The study treated patients with routine chemotherapy before and after liver surgery with or without cetuximab. The aim was to see whether the addition of this treatment would reduce the chance of the cancer getting worse or coming back after the operation. Unfortunately the trial produced an unexpected result such that patient's cancer came back sooner in the group receiving cetuximab. It is imperative that we conduct further research in order to understand why this happened.At the time of agreeing to participate in the trial, patients were also asked to give consent for their tissue to be used for studies in the future. These include redundant formalin fixed samples of their original bowel cancer and samples from their liver operation. This tissue now forms a vital resource for us to conduct laboratory based studies to try and explain this trial result. MicroRNAs are a recently discovered form of genetic material. They are expressed in healthy tissue, but corrupted in cancer. Our preliminary data shows that the level of a particular micro RNA, miR-31, expressed by the bowel cancers of patients in the New EPOC study may correlate with how they responded to treatment with cetuximab. The aim of my project is to study the mechanism behind this observation, that is the role of miR-31 in the response of a bowel cancer to the growth factor inhibitor cetuximab. Our preliminary work certainly suggests that it is likely to play an important role, but at present we do not know exactly which genes it is controlling. We will explore the mechanism by which miR-31 influences the progression of bowel cancer using tried and tested laboratory techniques which enable us to quantify cancer invasion and metastasis development. We will also use a mouse model to replicate the treatments used in the New EPOC study in order to dissect whether it was a particular combination of treatments, e.g. liver surgery combined with the growth factor inhibitor, that was detrimental. This project has key implications for the treatment of patients with bowel cancer in the future. The current restriction of the use of cetuximab to patients without a genetic change in their tumours called a KRAS mutation has proven insufficient in a number of studies, including New EPOC, to predict benefit. Determining the functional role of miR-31 in regulating the response of bowel cancer to growth factor blockers would enhance our understanding of which patients would benefit from these treatments, and assist in rationally selecting patients for use of targeted drugs. This, together with validation of miR-31 as a predictor of response in other trials, may permit the development of a test to allow better patient selection in the future thereby sparing those that will not likely benefit from the associated toxicities and loss of opportunity to receive other treatments. In the longer term it may open up new therapeutic opportunities for bowel cancer, and given the substantial costs of this targeted therapy provide health economic advantages also.