Using a novel epigenetic therapy to drive differentiation of atypical teratoid rhabdoid cells and facilitate immunotherapy
Atypical teratoid rhabdoid tumor (ATRT) is the most common malignant brain tumor of babies. We use very intensive chemotherapy, including stem cell transplant and even radiation, but we only cure a minority of patients. Those we do cure have life-long development and learning problems. We desperately need new therapies. Our current treatment does not address the root cause of ATRT, which is due to loss of function of a gene that helps cells decide when they should grow and when they should differentiate or mature. Mutation in this gene causes ATRT tumor cells to get stuck in an immature state and keep growing. There is a new drug, called corin, that reverses the block in maturation found in ATRT. When we treat ATRT tumor cells with corin, they stop growing and mature into brain cells. Corin also causes ATRT cancer cells to increase the levels of pro-inflammatory proteins, which means that corin could help to make the tumors more sensitive to immune therapy. This new therapy uses the patient's own immune system to attack their cancer. This innovative new drug could help us to find a new way to treat patients with ATRT.
Project Goals
The goal of the project is to find a partner drug that works well with corin to increase the number of tumor cells that are maturing into brain cells. We will also investigate if there are partner drugs that can enhance the amount of inflammatory proteins that are increased by corin. We find that another epigenetic drug that works in a different way from corin also increases differentiation and inflammatory markers in ATRT cells. Our goals are 1) to rigorously test if corin will work well with candidate partner drugs to promote differentiation and 2) to confirm that corin increases inflammatory proteinsin ATRT. Together these projects can help us advance an innovative new drug as a paradigm-shifting therapy for ATRT patients who desperately need therapies.
