Identifying opportunities for repurposing of approved drugs to new cancer indications using genetic and observational approaches

背景：遗传学方法在优选疾病治疗靶点方面发挥着重要作用。孟德尔随机化是一种流行病学技术，利用种系基因型的随机分布和固定性质来确定干预目标与疾病之间的因果关系。一个令人兴奋的应用领域是“孟德尔随机化药物再利用”——仅使用疾病全基因组关联研究（GWAS）的结果就能发现现有药物的新适应症。就癌症而言，这可适用于现有的肿瘤药物（即批准用于治疗一种癌症的药物，可重新用于治疗另一种癌症）或非肿瘤药物（例如批准用于治疗心血管疾病的药物，可重新用于治疗癌症）。与MR一起，观察性研究可以通过采用“目标试验”框架来估计药物使用对癌症生存的影响。这种方法包括将随机试验的设计原则应用于观察性研究，以最大限度地减少偏差和混淆的主要来源。靶试验分析中MR结果的重复可以为现有癌症治疗药物的再利用提供进一步的支持。在这个项目中，学生将应用核磁共振和“目标试验”方法来研究药物重新用于新的癌症适应症的机会。方法：使用影响蛋白质的基因组区域作为药物代理，学生将测试所选药物是否与癌症生存相关（孟德尔随机化方法）。后一项分析的结果将在临床实践研究数据链的一项“目标试验”观察性研究中得到复制。临床实践研究数据链是一个包含多达1600万患者匿名记录的初级保健数据库。总体研究结果将用于确定癌症治疗的优先顺序。

Background: Genetic approaches play an important role in prioritising therapeutic targets for disease treatment. Mendelian randomization (MR) is an epidemiological technique that exploits the random distribution and fixed nature of germline genotypes to identify causal relationships between intervention targets and disease. An exciting area of application is "drug repurposing Mendelian randomization" - where new indications are found for existing drugs using only the results from genome-wide association studies (GWAS) of disease. In the context of cancer, this could be applied to existing oncological medications (i.e. drugs approved to treat one type of cancer that are repurposed for the treatment of a different cancer) or non-oncological medications (e.g. drugs approved to treat cardiovascular disease that are repurposed for treatment of cancer). Along with MR, observational studies can be used to estimate the effects of medication use on cancer survival by employing a "target trial" framework. This approach involves applying design principles from randomised trials to observational research to minimise key sources of bias and confounding. Replication of findings from MR in target trial analyses can provide further support for the repurposing of existing drugs for cancer treatment. In this project, the student will apply MR and "target trial" approaches to investigate opportunities for repurposing of drugs to new cancer indications.Methods: Using regions of the genome that influence proteins as drug proxies, the student will test if selected drugs are associated with cancer survival (a Mendelian randomization approach). Findings from the latter analyses will be replicated in a "target trial" observational study of the Clinical Practice Research Datalink, a primary care database of anonymised records in up to 16 million patients. Overall findings will be used to prioritise treatments for cancer.