Project 458334

Li-Fraumeni Syndrome (LFS) is a genetic condition which drastically increases the risk of developing a spectrum of early-onset cancers. 1 in 5000 people are affected by LFS, and 80% of LFS patients are diagnosed with cancer before age 50. The Hospital for Sick Children has developed a surveillance protocol for the early detection of tumors in LFS patients worldwide; however, the success of this protocol is hindered by variations in patient presentation, including age of tumor onset. Furthermore, endless cycles of screening impose an immense psychosocial burden on patients throughout their lives. While strides have been made in treating LFS cancers once they develop, there remains an important clinical need for better prediction of tumor onset in order to improve treatment outcomes. Recent evidence suggests that metabolism may be altered in LFS, and there is abundant evidence showing that targeting metabolism may provide new strategies for cancer treatment. For example, metformin, a commonly prescribed diabetes drug, has been associated with lower cancer risk, and one study identified changes in the blood profiles of LFS patients who were treated with metformin. While it is well known that blood harbours a wealth of dynamic information which can be used to monitor disease, dynamic changes in the blood metabolomes of LFS patients have not been studied. To this end, we hypothesize that the blood metabolome can be characterized to predict tumor onset in LFS. To address this hypothesis, I will be longitudinally profiling the blood metabolomes of pediatric LFS patients and mice, both treated and untreated with metformin. This dynamic information will be integrated to understand whether tumor onset can be predicted using patients' blood. Overall, this work will address the need for a better understanding of the physiology of tumor development in LFS.