Mechanism-guided drug repurposing to accelerate the development of novel therapies for oral squamous cell carcinoma (OSCC)

预计到2020年，全球将有大约833,000人受到头颈部鳞状细胞癌(HNSCC)的影响。亚洲人占这些病例的80%以上。口腔鳞状细胞癌(OSCC)是HNSCC中最常见的一种。口腔鳞状细胞癌缺乏有效的治疗方法，导致口腔鳞癌患者的复发率和死亡率很高，迫切需要找到新的方法，以更快地开发治疗方案。在惠康·桑格研究所(WSI)和马来西亚癌症研究中心(CRM)的战略合作中，我们成功地使用了强大的基因编辑技术，利用主要来自亚洲OSCC患者的OSCC细胞系模型识别了维持癌细胞存活的基因。然而，由于新药开发既耗时又昂贵，重新调整现有抗癌药物的用途以针对口腔鳞癌可能会缩短为口腔鳞癌寻找新疗法所需的时间。不幸的是，口腔鳞状细胞癌细胞株的药物敏感性数据在促进药物再利用方面存在显著差距，特别是来自亚洲患者的药物敏感性数据。在这个项目中，我们将测试我们独特的口腔鳞癌细胞系对&gt；300临床相关药物的敏感性。这些信息与我们以前项目中的基因重要性数据相结合，将构成一个全面的机制引导的口腔鳞癌药物再利用资源，这将导致一个强有力的方法来确定可以重新用于口腔鳞癌治疗的候选药物。此外，这种方法还将使我们能够深入了解癌症患者的耐药机制，这可能导致测试可能会更有效的药物组合。我们的发现对扩大口腔鳞状细胞癌患者的治疗选择以及减轻马来西亚和其他国家口腔鳞癌患者的经济负担具有重要影响。

Approximately 833,000 individuals are expected to be affected by head and neck squamous cell carcinoma (HNSCC) worldwide in 2020. Asians make up more than 80% of these cases. Squamous cell carcinoma of the oral cavity (OSCC) is the most common form of HNSCC. The lack of effective therapies for OSCC has led to high recurrence and mortality rates among OSCC patients, and there is a pressing need to identify new approaches that can lead to the more rapid development of therapeutic options. In a strategic collaboration between the Wellcome Sanger Institute (WSI) and Cancer Research Malaysia (CRM), we have successfully used powerful gene-editing techniques to identify genes that keep cancer cells alive utilising OSCC cell lines models derived mostly from Asian OSCC patients. However, as de novo drug development is time-consuming and costly, efforts to repurpose existing anti-cancer drugs to target OSCC could shorten the time required to identify new therapies for OSCC. Unfortunately, there is a significant gap in the availability of drug sensitivity data on OSCC cell lines to facilitate drug repurposing, particularly from Asian patients. In this project, we will test the sensitivity of our unique collection of OSCC cell lines to >300 clinically relevant drugs. This information in combination with gene essentiality data from our previous project will make up a comprehensive mechanism-guided drug repurposing resource for OSCC that would result in a robust approach to identify candidate drugs that could be repurposed for OSCC treatment.Furthermore, this approach will also enable us to gain insights into the mechanism of drug resistance in cancer patients which may lead to the testing of drug combinations that could be more efficacious. Our findings have critical impact on expanding the therapeutic options for OSCC patients and to alleviate the economic burden of OSCC patients in Malaysia, as well as in other countries.