Utilizing chromatin directed inhibitors to regulate gene expression in Ewing sarcoma for therapeutic benefit
Ewing sarcoma is the second most common bone cancer in children, and the treatment of Ewing sarcoma continues to rely on traditional chemotherapy, surgery, and radiation. Unfortunately, children who have Ewing sarcoma that returns after initial therapy or whose disease has spread to other places in their body, a process known as metastasis, often do not survive their disease. Immunotherapies are new approaches to treating cancer using the patient’s own immune system. One promising immunotherapy option modifies a patient’s own T-cells to express a Chimeric Antigen Receptor (CAR), which allows the cells to detect specific tumor cell and eliminate their cancer. CAR T-cell therapy has revolutionized the treatment of blood cancers and holds great promise for treating children with solid tumors, such as Ewing sarcoma. However, pediatric solid tumors lack consistent targets, which reduces the potential therapeutic benefit of CAR-T cells. Gene expression changes in the tumor determine if a cancer cell contains a target or not. Fortunately, recently discovered molecules hold the potential to modify these gene changes. Therefore, this project seeks to identify new medicines to enhance CAR-T cell therapy for pediatric solid tumors.
Project Goal:
This project seeks to improve the treatment of Ewing sarcoma by utilizing small molecules to alter how the cancer cells read their DNA, known as gene expression. The first goal of this project will investigate the ability of the molecules tazemetostat and entinostat to force Ewing sarcoma cells to make the cellular target “GD2”, which can then allow CAR-T cells to detect and eliminate the cancer cells more efficiently. If successful, this part of the project will lay the groundwork for improving the implementation of GD2-targeted CAR-T cells, which are currently being investigated in multiple clinical trials nationwide. The second goal of this project will investigate the ability of tazemetostat and entinostat to reduce the ability of Ewing sarcoma cells to metastasize, or spread, to other parts of the body.
