Targeting DNA replication stress in Ewing sarcoma

Ewing sarcoma is the second most common childhood bone cancer. It is usually diagnosed in during puberty, when the cells of the body are dividing rapidly. Often, it grows in long bones, like the thighbone or the shinbone. It is also sometimes found in hipbones. Ewing sarcoma can be hard to treat, especially if the tumor has grown outside its original location. In addition, even patients whose cancer is cured often experience uncomfortable and long-lasting side effects. Thus, finding new treatments is an important area of ongoing research.

My thesis work focuses on a promising combination of two types of chemotherapy drugs for Ewing sarcoma treatment. One kind of drug prevents cells from making new DNA building blocks (RNR inhibitors), while the other keeps cells from fixing damaged DNA (ATR-CHK1 inhibitors). While both types of drugs are good at killing Ewing sarcoma cells, they are most effective when combined. To make sure we use these treatments as best as possible, it is important to know how they work. This is the main purpose of the research I have done, which identified that RNR inhibitors kill Ewing sarcoma cells by targeting the production of DNA building blocks, rather than through an unexpected pathway. I also identified several genes which, if mutated, might prevent tumors from dying after treatment with either RNR or ATR-CHK1 inhibitors. This information will hopefully allow researchers to have additional treatments lined up to kill tumors which don’t respond to those drugs. Overall, my work is meant to provide helpful information on a potential new treatment for patients with Ewing sarcoma.