The cell death regulator FLIP: evaluation of novel inhibitors in colorectal cancer

结直肠癌是西方世界癌症相关死亡的第二大原因，预计随着西方社会人口的老龄化，这种疾病造成的全球健康负担将会增加。因此，迫切需要改进治疗这种疾病的方法。此外，重要的是新的治疗方法是个性化的；这意味着它们针对的是最有可能受益的患者。这不仅对患者很重要，对苦苦挣扎的医疗系统也很重要，因为个性化癌症药物意味着他们可以省去无效治疗的财务成本，这些治疗可能只会产生毒副作用，需要额外昂贵的患者护理。最近，我们发现，结直肠癌患者的重要亚群从当前的治疗策略中受益甚微。使用现代技术可以很容易地识别这些亚群，这些技术可以识别导致癌症的基因突变，以及人体自身的防御机制(免疫系统)对癌症存在的警觉程度。在这项提案中，我们的目标是找出更好的方法来治疗这些患者亚群，使用一种新型药物，该药物针对癌细胞用来在化疗中存活的特定机制。我们的初步证据表明，将这种药物与已有的化疗药物联合使用，将通过以下方式提高那些没有从当前治疗中受益的结直肠癌患者的生存率：1.提高标准化疗药物的疗效。重新激活免疫系统以攻击癌症。该项目将使用临床相关的实验方法和最先进的技术来了解新药杀死癌细胞和重新激活人体免疫系统的分子机制。总体目标是在患者身上测试这些新疗法。在这方面，我们很幸运有理查德·威尔逊教授作为我们的主要合作者之一。理查德是一名临床学者，在早期临床试验方面拥有丰富的经验，特别是在结直肠癌方面。通过Richard在这个项目中的参与以及他在多个国内和国际结直肠癌临床试验网络中的角色，我们将能够迅速将实验室中最有希望的发现转化为患者的试验。总之，这个项目将为旨在提高结直肠癌患者存活率的新的临床试验奠定基础。此外，这些结果还可能对改进其他一些癌症的治疗产生影响，这些癌症是由导致结直肠癌的相同基因突变引起的；这些癌症包括胰腺癌和某些形式的肺癌。

Colorectal cancer is the 2nd leading cause of cancer-related death in the Western World, and the global health burden caused by this disease is forecast to increase as the populations of Western society continue to age. Thus, improved approaches to treat this disease are urgently needed. Moreover, it is important that new therapies are personalised; this means targeting them to patients most likely to benefit. This is not only important for patients, but also for struggling healthcare systems, as personalising cancer medicine means that they are spared the financial costs of ineffective therapies that may only produce toxic side-effects that require additional, costly patient care.Recently, we have found that significant subgroups of colorectal cancer patients benefit little if at all from current treatment strategies. These subgroups are readily identifiable using modern techniques which can identify the gene mutations that cause the cancer and the extent to which the body's own defence mechanisms (the immune system) are alert to the presence of the cancer. In this proposal, we aim to identify better ways of treating these patient subgroups using a new type of drug that targets a particular mechanism used by cancer cells to survive chemotherapy. Our preliminary evidence suggests that using this type of drug in combination with established chemotherapies will improve the survival rates of colorectal cancer patients in those patients, who do not benefit from current treatment by:1. Enhancing the efficacy of standard chemotherapy agents.2. Reactivating the immune system to attack the cancer. The project will use clinically relevant experimental approaches and state-of-the-art techniques to understand the molecular mechanisms by which the new drugs work to kill cancer cells and reactivate the body's immune system.The overall goal is to test these new treatments in patients. In this regard, we are fortunate to have Prof Richard Wilson as one of our key collaborators. Richard is a Clinical Academic with enormous experience in early phase clinical trials, particularly in colorectal cancer. Through Richard's engagement in this project and his role in a number of national and international colorectal cancer clinical trials networks, we will be able to rapidly translate the most promising findings from the lab into trials in patients.In summary, this project will lay the foundations for new clinical trials aimed at improving the survival of colorectal cancer patients. In addition, these results could also have implications for improving the treatment of a number of other cancers which are caused by the same gene mutations that cause colorectal cancer; these include pancreatic cancer and certain forms of lung cancer.