Targeting alternative lengthening of telomeres in cancer

Telomeres have a double role in neoplasia. These highly conserved repetitive nucleoprotein structures that protect the ends of chromosomes safeguard somatic cells from tumorigenic mutations and prevent cancer. However, most tumors bypass replicative senescence and support malignant cell growth via the activation of telomere maintenance mechanisms (TMM). Underpinning their important role in neoplasia, DNA damage responses lie at the epicenter of these seemingly contradictory but highly interrelated telomere functions. It is well established that the great majority of cancers sustain capacity for uncontrolled continuous cell proliferation through the activation of reverse transcriptase telomerase. However, approximately 10-15% of human neoplasms maintain their telomeres via at least two distinct homologous recombination-mediated pathways, termed Alternative Lengthening of Telomeres (ALT). Although much rarer and less well understood than telomerase activity, ALT is considered equally important, not only because it involves a subset of highly aggressive tumors, but also due to its putative engagement as a resistance mechanism that may burden all current and future onco-therapies based on telomerase suppression. Significant progress has been made in understanding the underlying mechanisms of ALT. Epigenetic modifications, telomere-interacting factors, and homology-driven DNA damage repair have been implicated in the ALT pathway. These advances hold promises for the development of novel, highly efficient therapies that target TMM in malignancy.

Sarantis Gagos received his PhD from Athens Medical School. He was Postdoctoral Fellow at the Laboratory of Cellular Genetics, M.D. Anderson Cancer Center, University of Texas, Houston, USA. Dr Gagos is certified by the American Board of Medical Specialties as a “Clinical Cytogeneticist”. Dr Gagos was Director of the Laboratory of Clinical Cytogenetics of the University Hospital of Geneva, Switzerland. Current research of Gagos group in the Biomedical Research Foundation of the Academy of Athens, Greece is focused on Chromosomal Instability and the basic mechanisms of recombinatorial telomere maintenance in cancer.