| Description |
Ewing sarcoma is a malignant disease of young people that arises most frequently in bones of the femur and pelvis. The disease most often afflicts adolescents, creating physical, emotional and developmental challenges during an individual's most formative years. Mainstays of therapy include surgery and chemotherapy, meaning that survival may come at very high costs - amputation and lifelong disability. Those whose suffer metastasis or relapse must confront a poor prognosis. This is due in part to a lack of effective therapeutic options capable of destroying cancer at the cellular and molecular levels. To this end, molecular research continues to pursue greater understanding of the underlying biology of these tumors. The principal genetic lesion in Ewing sarcoma is a translocation that fuses chromosomes 11 and 22, giving rise to an oncogenic fusion protein known as EWS/FLI. EWS/FLI causes massive transcriptional misregulation, generating a gene expression program that transforms cells into cancer. Studies of transcriptional consequences of EWS/FLI misregulation have identified numerous genes that are necessary - but not sufficient - for tumorigenesis of Ewing sarcoma. These efforts have produced several candidates for molecular therapies for this malignancy, but no new therapies have yet reached the clinic. Research continues this pursuit, and hope persists. The work presented in this thesis is some of the first efforts to investigate the metabolic underpinnings of Ewing sarcoma. Specifically, these data provide preliminary insights into the effects that EWS/FLI has on misregulating metabolism, generating a program of biosynthesis that promotes and/or contributes to oncogenesis in these tumors. Numerous metabolic pathways are altered upon silencing of EWS/FLI, suggesting that EWS/FLI drives expression changes of key enzymes involved in metabolic processes. These data appear to indicate that generating a pro-oncogenic metabolic program is a key part of how EWS/FLI drives oncogenesis. Due to the fact that metabolic enzymes are generally amenable to pharmacological modulation, these findings offer new hope to the pursuit of a molecular therapy for Ewing sarcoma. |
