Development of combination therapies for childhood cancers

More than 200 children are diagnosed with high-risk cancer in Australia each year. Over 140 of these children still lose their life due to the occurrence of resistance to traditional chemotherapy. Cancer immunotherapy is an emerging approach for untreatable cancers. The key mechanism of the immune system for combating cancer is recognition of peptides exclusively presented on the tumour surface in complex with Human Leukocyte Antigen (HLA) molecules. Losing the ability to present peptide antigens through HLA loss, facilitates immune evasion in cancer. This reduced/loss of HLA class surface expression is caused by an impaired expression of key components of the antigen processing machinery (APM). One of the main mechanisms of silencing of the APM is epigenetic dysregulation. Evidence suggests that pharmacological epigenetic modifier drugs, including histone deacetylase inhibitors (HDACi) can drive re-expression of APM components and restore HLA class-I surface expression. In this project, we will study the effect of epigenome regulator drugs on the expression of HLA molecules in childhood solid tumours with poor outcomes. Also, as a consequence of HLA expression restoring; we will investigate cancer antigen derived peptides that present by HLA molecules as potential targets for cancer immunotherapy.