Funding: US Department of Defense Idea Award with Special Focus.
Synopsis: Mesothelioma is an aggressive and incurable cancer caused primarily by asbestos exposure. The prognosis is very poor, with five-year survival rates of only 3% for men and 12% for women. Immunotherapy is an exciting treatment for mesothelioma because it can cause long term tumour shrinkage. However, it only works exceptionally well for approximately 20% of cancer patients. The goal is to improve the number of mesothelioma patients who benefit from immunotherapy. Expression of genes are regulated by changes made to the DNA without altering the underlying nucleotide sequence. Some modifications can switch a gene on while others switch genes off. In mesothelioma tumours, important immune genes are often switched off, which may explain why immunotherapy does not work well in some patients. Current epigenetic modifying drugs do not work well in mesothelioma because they lack gene-specificity, and potentially cause high toxicity. Our lab has developed a new, targeted technology that allows us to manipulate the epigenetic state of immune genes that will improve immunotherapy responses in patients. This project will test this technology in mesothelioma tumours. We will switch on important immune genes, and use mouse models to test if immunotherapy will work better against these modified tumours. The long-term application of our research is to use this technology with immunotherapy for mesothelioma patients, with the goal of turning a non-responding patient to a responding one.