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

预计到2020年，全球约有83.3万人患有头颈部鳞状细胞癌（HNSCC）。亚洲人占这些病例的80%以上。口腔鳞状细胞癌（OSCC）是最常见的口腔鳞状细胞癌。OSCC缺乏有效的治疗方法，导致OSCC患者的高复发率和死亡率，迫切需要确定新的方法，从而更快地开发治疗方案。在威康桑格研究所（WSI）和马来西亚癌症研究所（CRM）的战略合作中，我们成功地使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，鉴定出保持癌细胞存活的基因。然而，由于新药物开发耗时且成本高昂，将现有抗癌药物重新定位于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重大差距，以促进药物再利用，特别是来自亚洲患者。在这个项目中，我们将测试我们独特收集的OSCC细胞系对300种临床相关药物的敏感性。这些信息与我们之前项目的基因重要性数据相结合，将构成一个全面的机制指导的OSCC药物再利用资源，这将导致一种强有力的方法来确定可用于OSCC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，这可能会导致测试更有效的药物组合。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.