The identification of genetic vulnerabilities in head and neck cancers for the development of novel therapies.

Every year ~370,000 of the world population will die of head and neck squamous cell carcinoma (HNSCC), and of these more than 80% will be from the Asian sub-continent. In Malaysia, HNSCC is the second commonest form of cancer. Less than 50% of HNSCC patients will survive beyond 5 years after diagnosis, largely due to a lack of effective therapies for this cancer. There is compelling evidence that identifying the genes that are responsible for the survival and growth of cancer cells can help us develop new drugs, and more importantly determine which existing drugs are most effective for specific patients. Here, using cancer cells that were derived from Asian HNSCC patients, we will use newly developed powerful gene editing techniques to identify critical genes that are responsible for cancer survival, and where inhibiting these would result in cancer cell death or growth arrest. The identification of genes that are essential for cancer cell survival will result in identification of relevant existing drugs that could be re-purposed for the treatment of HNSCC. This approach would shorten the drug development markedly as the safety and efficacy profiles of these would already be well-documented. In addition, the knowledge of the genes that drive HNSCC would afford an opportunity to develop novel drugs that could be effective in the treatment of HNSCC.

The global cancer burden is expected to double by the year 2030 and this will disproportionately affect the Asian continent. Head and neck squamous cell carcinoma (HNSCC) is endemic in Asia, and it is one of the top 3 cancers in Malaysia. Long-term survival of less than 50% and limited approved therapies for HNSCC underscore the urgent need for the development of novel and effective therapies. While the mutational landscape of HNSCC is now well established, the ability to identify the targetable component of the cancer genome will accelerate translation of these knowledge into clinical benefit. A major focus in the development of new cancer therapies has been the identification of essential genes that are critical for the survival of cancer cells, and where loss or inactivation of these can result in cell death or growth arrest.

This project will use state-of-the art biological models, genome-wide CRISPR/Cas9 lethality screens and next-generation sequencing, to address this major health problem in Asia. We will use experimental and computational approaches to identify essential genes for HNSCC and specific pharmacologic inhibitors that could target these genes. The successful completion of this project will form the basis of developing novel targeted drugs for HNSCC as well as re-purposing existing therapies currently used to treat other cancer types.

The identification of molecular therapies requires a good understanding of cancer biology and access to technology that enables the systematic evaluation of the role of each gene as a potential driver of cancer development. This partnership between Wellcome Trust Sanger Institute (WTSI) and Cancer Research Malaysia (CRM) will bring together cancer researchers who have a deep understanding of HNSCC and considerable experience working with this disease and individuals who have utilized powerful gene editing technologies to dissect the contribution of each gene to the cancer development process.

This partnership will immediately benefit the CRM head and neck cancer groups and their network of collaborators by enabling new technological advancements to be applied in identifying critical genes in cancers that are important in Malaysia and the wider region. This study will result in the training of two post-doctoral research scientists and a MSc student. The training of a researcher from CRM (Dr Vivian Tiong) has already been initiated through a Union for International Control/International Cancer Research Technology Transfer (UICC/ICRETT) fellowship in 2015 where Dr Tiong spent 10 weeks in Dr McDermott's laboratory in WTSI. It is anticipated that this proposal will generate local expertise in Malaysia in the use of genome-wide CRISPR lethality screens that at a future date could be extended to other cancer types in addition to HNSCC.

The results generated from this study will additionally benefit scientists and clinicians working on head and neck cancers and other cancers in general as the data will serve as a valuable resource to inform researchers about the possible genes that are responsible for maintaining cancer cell survival. While this study focuses on head and neck cancers, emerging evidence suggests that molecular pathways that are critical in one type of cancer could also be important in other cancer types.

Furthermore, such large data-sets would also be beneficial to pharmaceutical companies designing and developing therapeutic interventions. As the CRISPR/Cas9 technology is relatively new, the data generated here would add to existing information on essential genes in cancer, particularly those that can be targeted for cancer control. In the longer term all the available data taken together could accelerate the development of effective treatment strategies for HNSCC. This could be an avenue that provide economic competitiveness to the United Kingdom as drugs for the treatment of HNSCC is still very limited.

While it is not possible to include clinical validation within the limited duration of this 2-year study, we would hope that the results of this study will result in the identification of potential targets in HNSCC, both those where there are existing drugs and those that are truly novel . For the former, the long-term goal would be to re-purpose existing drugs for use in HNSCC within 3 years. This would be a significant advancement in the clinical field of HNSCC as there is currently only one targeted therapy approved for therapeutic use. For truly novel targets that are validated, an additional period of research that involves collaboration with medicinal chemistry (for chemical probe design) and in vivo model groups would be desirable. This would of necessity have to be the focus of a new research proposal.