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.

TRF1 and TRF2: pioneering targets in telomere-based cancer therapy

“…One approach in targeting the shelterin complex involves the development of small molecule inhibitors that specifically bind to these proteins. Compounds targeting TRF1 and TRF2 have shown promise in preclinical studies (Ivancich et al 2017 ; Di Nunno et al 2023 ). For instance, inhibitors of TRF1 and TRF2 have been demonstrated to destabilize the shelterin complex, leading to telomere dysfunction and reduced cancer cell proliferation (Smith et al 2011 ).…”