Telomere and Telomerase Therapeutics in Cancer

Abstract

Telomerase is a reverse transcriptase capable of utilizing an integrated RNA component as a template to add protective tandem telomeric single strand DNA repeats, TTAGGG, to the ends of chromosomes. Telomere dysfunction and telomerase reactivation are observed in approximately 90% of human cancers; hence, telomerase activation plays a unique role as a nearly universal step on the path to malignancy. In the past two decades, multiple telomerase targeting therapeutic strategies have been pursued, including direct telomerase inhibition, telomerase interference, hTERT or hTERC promoter driven therapy, telomere-based approaches, and telomerase vaccines. Many of these strategies have entered clinical development, and some have now advanced to phase III clinical trials. In the coming years, one or more of these new telomerase-targeting drugs may be expected to enter the pharmacopeia of standard care. Here, we briefly review the molecular functions of telomerase in cancer and provide an update about the preclinical and clinical development of telomerase targeting therapeutics.

Keywords: targeted therapy; telomerase; telomeres.

Figure 1

Overview of telomerase therapeutic strategies. Several telomerase-based therapeutic approaches have been developed: (A) G-quadruplex stabilizers prevent unwinding of the quadruplex, making the 3’ overhang inaccessible to telomerase; (B) Telomeric oligos (T-oligo) mimic uncapped telomeres and elicit a DNA damage response; (C) Tankyrase inhibitors inhibit dissociation of TRF1 from telomeres, rendering them less accessible to telomerase; (D) Direct inhibition of telomerase enzymatic activity via an oligonucleotide (Imetelstat) that binds TERC template; (E) Telomerase interference (MT-TERC) that reprograms telomerase to add mutant telomeric repeats that elicit a DNA-damage response; (F) TERT promoter driven oncolytic viruses that cause tumor-specific cell lysis; (G) Suicide gene therapy that employs TERT or TERC promoter-driven expression of enzymes that convert pro-drugs to active cytotoxic molecules; (H) Telomerase vaccines that induce cytotoxic T lymphocyte by either direct inoculation or ex vivo activation.