Targeting Telomerase for Cancer Therapy

The ribonucleoprotein, telomerase, prevents genomic instability by adding telomere repeats at the end of chromosomes. Although the telomerase RNA component (TERC) is ubiquitously expressed in mammalian cells, the telomerase reverse transcriptase subunit (TERT) is not expressed at easily detectable levels in most somatic cells but is expressed in most cancer cells. Targeting the up-regulation of TERT expression and/or enzymatic activity has gained considerable attention as a potential cancer therapy. Agents targeting the TERT component include nucleoside and nonnucleoside analogs as well as molecular inhibition of TERT using dominant negative protein expression or by ribozymes. Expression of the RNA component of telomerase has been targeted using RNA oligonucleotides. Additionally, peptide vaccines against telomerase have also been studied. Although several telomerase inhibitors have begun initial clinical trials for cancer therapy, none so far have entered clinical practice. Several aspects of telomere biology and telomerase action must be considered in designing anti-telomerase strategies for cancer treatment. These include expression of telomerase in normal somatic cells, the potential for selection of ALT (alternative lengthening of telomeres) clones, and the time-lag that is observed between initiation of treatment and appearance of cytopathic effect. However, knowledge of telomerase functions beyond telomere maintenance can provide insight into methods that may overcome limitations of telomerase- based therapies.