Professor Susan Burchill, St James's University Hospital, Leeds (£38,212)
Overcoming the challenges of studying telomerase biology in clinical samples; towards understanding tumour heterogeneity, telomerase and clinical significance in ESFT.
Telomerase activity is one of the most important biological factors in the development of many cancers, including ESFT. During cell division ESFT express telomerase to maintain telomere length and so escape cell cycle induced attrition of telomeres and senescence. Using in vitro models of ESFT we have recently shown that expression of hTR regulates telomerase activity under normal growth conditions, however this usual tight regulation of telomerase activity appears to be lost when cells are incubated in hypoxia. This may be associated with the development of drug resistance, one of the most difficult therapeutic challenges. These observations suggest that hTR and or telomerase activity may be useful targets for the development of therapeutic strategies in ESFT. However little is known about telomerase and regulators of its activity in primary ESFT. This is partly due to lack of standardised assays and tumour heterogeneity. Therefore the primary aim of the proposed study is to establish the heterogeneity of telomerase activity, hTERT isoforms and hTR expression in primary ESFT using standardised assays; in situ assays will be developed and validated to establish if expression is uniform across the tumour or isolated to specific cells. Secondly, the hypothesis that hTR may regulate telomerase activity to modulate telomere length will be examined, and the effect of proliferation and tumour microenvironment on this relationship explored. These studies may identify important targets for the development of new therapeutic strategies in ESFT, and increase understanding of tumour heterogeneity and the development of drug resistance in this aggressive disease.
