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

预计2020年全球约有833，000人受头颈部鳞状细胞癌（HNSCC）影响。亚洲人占这些病例的80%以上。口腔鳞状细胞癌（OSCC）是HNSCC最常见的形式。由于缺乏有效的治疗方法，OSCC患者的复发率和死亡率很高，因此迫切需要确定新的方法，以更快地开发治疗方案。在Wellcome桑格研究所（WSI）和马来西亚癌症研究所（CRM）之间的战略合作中，我们成功地利用强大的基因编辑技术，利用主要来自亚洲OSCC患者的OSCC细胞系模型来识别保持癌细胞存活的基因。然而，由于从头药物开发是耗时和昂贵的，重新利用现有抗癌药物靶向OSCC的努力可以缩短确定OSCC新疗法所需的时间。不幸的是，在OSCC细胞系的药物敏感性数据的可用性方面存在显着差距，以促进药物再利用，特别是亚洲患者。在这个项目中，我们将测试我们独特的OSCC细胞系对超过300种临床相关药物的敏感性。这些信息与我们先前项目的基因必要性数据相结合，将构成一个全面的机制指导的OSCC药物再利用资源，这将导致一个强大的方法来识别可用于OSCC治疗的候选药物。这种方法还将使我们能够深入了解癌症患者的耐药性机制，这可能导致对药物组合的测试，更有效。我们的研究结果对扩大OSCC患者的治疗选择和减轻马来西亚以及其他国家OSCC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.