ImetelChat

TARGETING TERT: A PLAYER IN SEARCH OF AN AUTHOR At each cell division, telomeres become shorter; however, a specialized enzyme called telomerase provides the chromosome tips of additional DNA. Telomerase is a reverse transcriptase ribonucleoprotein enzyme coded by the TERT (telomerase reverse transcriptase) gene that copies the template RNA named telomerase RNA component (TERC) (Figure 3A). Telomerase critically ensures chromosome length and genomic stability during cell replication, with telomerase defects being, accordingly, associated with senescence and cellular death (6). Conversely, some mutations in the TERT promoter are oncogenic, resulting in cell immortalization and transformation. These mutations, firstly discovered in melanoma, include frequent cytidine-to-thymidine conversion and have been found at two genetic regions upstream of the transcriptional start site, specifically c.-124C>T and c.-146C>T (7) (Figure 3B).

A low rate of self-renewal in GBM histological samples has been correlated to high TERT expression in various currently low, and only imetelstat (GRN163L) has entered in clinical practice. Imetelstat is a competitive inhibitor of TERT that acts by hindering the binding of telomerase to DNA (12). Interestingly, in GBM, imetelstat has been shown to reduce cell proliferation both in vitro and in vivo. Importantly, the drug was observed to cross the blood–brain barrier (BBB) and reduce tumor growth in tumor-engrafted mice (13). In addition, the association of imetelstat with classical radiotherapy and temozolomide drastically reduced GBM tumor growth in vitro and in pre[1]clinical studies (12).

However, despite the promising results obtained, clinical trials have failed to prove imetelstat as effective on human solid tumors, probably because of the poor permeation of the drug into tumor tissues and for critical effects, such as several intracranial hemorrhages in phase II trial NCT01836549 (14).