Ewing-Like Sarcoma: Targeting the CIC-DUX4 Oncogene Through Epigenetic Regulators
Abstract
Cancer can develop from any tissue. The most common cancers develop from organs like the lung, breast, and prostate. More rarely, cancers develop from the bones and muscles, and they are called sarcomas. Some sarcomas like Ewing sarcoma respond well to standard cancer therapy like chemotherapy and radiation therapy. However, there are other sarcomas that under the microscope look just like Ewing sarcoma, but do not respond well to standard cancer therapies. These rare sarcomas are called Ewing-like sarcoma. We know that Ewing sarcoma and Ewing-like sarcoma are each caused when parts of two different proteins are joined together to create a fusion protein with cancer-causing properties. In Ewing-like sarcoma, the cancer-causing fusion protein is CIC-DUX4. How CIC-DUX4 causes sarcomas and why these sarcomas are so resistant to current cancer therapy is not known. In this proposal, we will use human sarcoma cell lines from Ewing-like sarcoma patients and dissect how CIC- DUX4 causes cancer. Using a genetic approach to deplete CIC-DUX4, we will test the idea that CIC-DUX4 rewires a cell to turn on genes that endow it with aggressive properties like increased proliferation and invasion. We will also use the same genetic approach to test the idea that for CIC-DUX4 to turn on these genes, specific co-activators like p300 are required. If this is the case, then this would be important, because p300 inhibitors are now being tested in clinical trials in patients with other diseases. Therefore, if this proposal is successful, we may discover a new way to treat Ewing-like sarcoma. In this proposal, we will also generate and characterize the first genetically engineered mouse model of sarcoma driven by the CIC-DUX4 fusion protein. We will use this new animal model to optimize current cancer therapies and test novel treatments for Ewing-like sarcoma.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210454
Entities
People
- David Kirsch
Organizations
- Duke University
- United States Army