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

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.

This study will represent a comprehensive mechanism-guided drug repurposing reference for OSCC, through the generation and integration of large-scale drug response and gene essentiality data on unique Malaysian OSCC models. About 300 clinically-relevant drugs at various doses will be tested on 21 OSCC cell lines, generating over 44,100 drug sensitivity estimates. This will address the significant gap in the limited large-scale drug response data that is currently impeding drug repurposing efforts for OSCC. The study will identify candidate drugs, providing opportunities to accelerate novel therapeutic development for OSCC. This approach could also provide clues to the mechanisms underlying drug resistance that will form the basis for novel drug combinations to increase efficacy. These discoveries would be published in international peer-reviewed journals, and the data made publicly accessible through the Sanger's Genomics of Drug Sensitivity in Cancer (GDSC) data (PMID:23180760).