Exploiting cell death for therapeutic advantage in the Ewing’s sarcoma family of tumours (ESFT).
ESFT are characterised by a gene rearrangement between the EWS gene on chromosome 22q12 and a member of the ETS family of transcription factors (Figure 1). They are most frequently diagnosed in adolescents and young adults between the ages of 10-25 years. Treatment intensification has improved outcome, but 30-40% of those with localised and 80% with metastatic disease still die due to disease progression.
Recurrence and metastases continue to pose the most difficult challenge for management and treatment of these solid cancers. Therefore our strategy has been to establish a comprehensive research programme, identifying and evaluating novel therapeutic targets for the treatment of metastatic and resistant disease. In addition we identify molecular markers to assess and monitor the efficacy of these potential treatments in the clinic.
Using this approach we have recently shown that ESFT are particularly sensitive to fenretinide induced cell death, which is effected through a reactive-oxygen species and a p38MAPK dependent pathway (Figure 2). Our preclinical studies have informed the design of a clinical trial incorporating fenretinide to treat metastatic disease in patients with ESFT.
The stress-activated kinase p38MAPK appears to play a central role in determining ESFT cellular fate. We are therefore investigating the regulation of this MAP kinase and its importance in initiation and execution of the cellular death cascade, with a view to exploiting this pathway for therapeutic advantage.
Figure 1: Characterising the genetic events and their impact on phenotype and
tumour behaviour is critical for our translational studies”
Figure 2: Histological evidence of fenretinide-induced death in ESFT; increased
phosphorylation of p38MAPK in treated tumours, consistent with the hypothesis
that p38MAPK is an effector of cell death in ESFT
Myatt SS, Redfern C and Burchill SA. p38MAPK-dependent sensitivity of Ewing’s sarcoma family of tumours (ESFT) to 4-hydroxy(phenyl)retinamide-induced death. Clin Cancer Res. 11(8):3136-48, 2005.
Burchill S.A. Ewing’s sarcoma: diagnostic, prognostic and therapeutic implications of molecular abnormalities. Journal of Clinical Pathology. 56, 96-102, 2003.
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