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

背景：遗传学方法在疾病治疗的优先治疗靶点方面发挥着重要作用。孟德尔随机化（MR）是一种流行病学技术，利用生殖系基因型的随机分布和固定性质来确定干预目标和疾病之间的因果关系。一个令人兴奋的应用领域是“药物再利用孟德尔随机化”-仅使用疾病的全基因组关联研究（GWAS）的结果为现有药物发现新的适应症。在癌症的背景下，这可以应用于现有的肿瘤药物（即批准用于治疗一种癌症的药物，重新用于治疗不同的癌症）或非肿瘤药物（例如批准用于治疗心血管疾病的药物，重新用于治疗癌症）。沿着MR，观察性研究可通过采用“靶向试验”框架来评估药物使用对癌症生存率的影响。这种方法涉及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倚和混淆的关键来源。在靶向试验分析中复制MR的结果可以为现有药物用于癌症治疗提供进一步的支持。在这个项目中，学生将应用MR和“靶向试验”的方法来研究药物再利用的机会，以新的癌症indication.Methods：使用基因组的区域，影响蛋白质作为药物代理，学生将测试，如果选定的药物与癌症生存（孟德尔随机化方法）。后者分析的结果将在临床实践研究数据链的“目标试验”观察性研究中复制，这是一个包含多达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优先治疗癌症。

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.