Identification and characterization of novel human telomere-related biomarkers that aid cancer management by improving patient diagnosis, treatment selection, response monitoring, and drug development
Coordinator: Robert NEWBOLD
Project Number: 200950
EC contribution: € 2,848,490.00
Telomeres are DNA-nucleoprotein structures that protect the ends of human chromosomes through the formation of a ‘cap’ that prevents exonucleolytic degradation, inter- & intra-chromosomal fusion and subsequent chromosomal instability. Telomerase, the ribonucleoprotein enzyme that maintains linear chromosomal DNA ends by the addition of TTAGGG repeats, is completely repressed or present only at low, tightly regulated levels in normal human cells as a safeguard against cancer. Normally, telomere shortening in the absence of sufficient telomerase leads to telomere uncapping, activation of a DNA damage response, and either replicative senescence or apoptosis. Paradoxically, however, under certain conditions (when damage response pathways are defective, eg through p53 gene mutation) unchecked telomere shortening can generate a chronic genomic instability that drives and accelerates clonal evolution and cancer progression. As a result, telomeres are dysfunctional in human cancers. Individual protein components of the core telomere higher-order structure (known as the telosome, or the ‘shelterin’ complex) represent highly promising candidates for novel biomarkers of telomere dysfunction and human cancer progression. In this project (‘TeloMarker’) we have assembled the most experienced and talented scientists in telomere biology in the EU into a collaborative research consortium that will identify, characterize and validate novel telomere-related biomarkers. Biomarker discovery will be based both on known telosomal components and newly discovered affiliated proteins, as well as on telomerase and its recruitment factors. Novel telomere-related cancer biomarkers promise radically to improve early diagnosis, patient treatment selection, prognostic evaluation, and outcome monitoring, as well as furnishing new molecular targets for the development of novel small molecule anti-cancer drugs.