The Biological and Clinical Role of the Telomerase Reverse Transcriptase Gene in Glioblastoma: A Potential Therapeutic Target?

Abstract

Glioblastoma IDH-wildtype represents the most lethal and frequent primary tumor of the central nervous system. Thanks to important scientific efforts, we can now investigate its deep genomic assessment, elucidating mutated genes and altered biological mechanisms in addition to its clinical aggressiveness. The telomerase reverse transcriptase gene (TERT) is the most frequently altered gene in solid tumors, including brain tumors and GBM IDH-wildtype. In particular, it can be observed in approximately 80-90% of GBM IDH-wildtype cases. Its clonal distribution on almost all cancer cells makes this gene an optimal target. However, the research of effective TERT inhibitors is complicated by several biological and clinical obstacles which can be only partially surmounted. Very recently, novel immunological approaches leading to TERT inhibition have been investigated, offering the potential to develop an effective target for this altered protein. Here, we perform a narrative review investigating the biological role of TERT alterations on glioblastoma and the principal obstacles associated with TERT inhibitions in this population. Moreover, we discuss possible combination treatment strategies to overcome these limitations.

Keywords: TERT; TERT inhibitor; glioblastoma; glioma.

Figure 1

Telomerase recruitment through interaction with shelterin complex. TPP1—tripeptidyl peptidase 1; TRF1 = telomeric repeat-binding factor 1; TRF2 = telomeric repeat binding factor 2; TIN2 = TRF1-interacting nuclear factor 2; POT1 = protection of telomeres protein 1; hTR = RNA template of TERT [14].

Figure 2

Regulation of TERT transcription through ETS transcription factor GABP. GABP tetramers, constituted by GABPα (DNA-binding subunit) and GABPβ1L (transactivating subunit) bind both the mutant E26 binding motifs and the normal motifs nearby. They are critical in activating the mutant TERT promoter.