title: Targeting the p53 Pathway in Ewing Sarcoma.
abstract: The p53 tumour suppressor plays a pivotal role in the prevention of oncogenic transformation. Cancers frequently evade the potent antitumour surveillance mechanisms of p53 through mutation of the TP53 gene, with approximately 50% of all human malignancies expressing dysfunctional, mutated p53 proteins. Interestingly, genetic lesions in the TP53 gene are only observed in 10% of Ewing Sarcomas, with the majority of these sarcomas expressing a functional wild-type p53. In addition, the p53 downstream signaling pathways and DNA-damage cell cycle checkpoints remain functionally intact in these sarcomas. This paper summarizes recent insights into the functional capabilities and regulation of p53 in Ewing Sarcoma, with a particular focus on the cross-talk between p53 and the EWS-FLI1 gene rearrangement frequently associated with this disease. The development of several activators of p53 is discussed, with recent evidence demonstrating the potential of small molecule p53 activators as a promising systemic therapeutic approach for the treatment of Ewing Sarcomas with wild-type p53.
authors.affiliation: Sarcoma Research Group, Discipline of Medicine, University of Adelaide and Hanson Institute, Frome Road, Adelaide, SA 5000, Australia.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Neilsen
authors.forename: Kathleen I
authors.initials: KI
authors.lastname: Pishas
authors.forename: David F
authors.initials: DF
authors.lastname: Callen
authors.forename: David M
authors.initials: DM
authors.lastname: Thomas