Telomerase-based Cancer Therapeutics: A Review on their Clinical Trials

Abstract

Telomeres are protective chromosomal ends that shield the chromosomes from DNA damage, exonucleolytic degradation, recombination, and end-to-end fusion. Telomerase is a ribonucleoprotein that adds TTAGGG tandem repeats to the telomeric ends. It has been observed that 85 to 90% of human tumors express high levels of telomerase, playing a crucial role in the development of cancers. Interestingly, the telomerase activity is generally absent in normal somatic cells. This selective telomerase expression has driven scientists to develop novel anti-cancer therapeutics with high specificity and potency. Several advancements have been made in this area, which is reflected by the enormous success of the anticancer agent Imetelstat. Since the discovery of Imetelstat, several research groups have contributed to enrich the therapeutic arsenal against cancer. Such contributions include the application of new classes of small molecules, peptides, and hTERT-based immunotherapeutic agents (p540, GV1001, GRNVAC1 or combinations of these such as Vx-001). Many of these therapeutic tools are under different stages of clinical trials and have shown promising outcomes. In this review, we highlight the current status of telomerase-based cancer therapeutics and the outcome of these investigations.

The Role of Alternative Lengthening of Telomeres Mechanism in Cancer: Translational and Therapeutic Implications

“…It has been reported that telomerase-positive tumors often exhibit shorter telomeres than normal surrounding tissue counterparts [5], as a consequence of the late reactivation of telomerase activity during tumorigenesis [11]. This observation, alongside the evidence that the enzyme is expressed in about 90% of human tumors [5,11], have provided compelling arguments to indicate that the enzyme is a suitable cancer-associated target [36]. Data from preclinical studies on the effects of telomerase inhibition have led GRN163L (a.k.a.…”

“…Data from preclinical studies on the effects of telomerase inhibition have led GRN163L (a.k.a. Imetelstat), a palmitoyl lipid-based thiophosphoramidate oligonucleotide inhibiting telomerase activity through competitive inhibition [36], to enter clinical trials as a single agent or in combination with conventional anticancer drugs for different malignancies (https://clinicaltrials.gov). Available data have demonstrated that the drug has limited therapeutic efficacy, though it was generally well-tolerated and with common side effects, such as neutropenia, thrombocytopenia, anemia, fatigue, etc.…”

“…Available data have demonstrated that the drug has limited therapeutic efficacy, though it was generally well-tolerated and with common side effects, such as neutropenia, thrombocytopenia, anemia, fatigue, etc. [36]. However, in brain tumor patients, the drug was administered for an average of only 2 weeks before toxicity occurred [37], and treatment interruption (i.e., medication vacation) led to rapid telomere lengthening and rescue of tumor growth [38].…”

Telomeres and Telomerase in the Development of Liver Cancer

“…For further reading, we refer to a recent excellent article, which discusses this topic in greater detail [162]. Furthermore, we refer to a recent review article, which summarizes clinical trials on telomerase-based cancer therapeutics [163].…”

Penetration into Cancer Cells via Clathrin-Dependent Mechanism Allows L-Asparaginase from Rhodospirillum rubrum to Inhibit Telomerase

“…Telomerase activity allows tumor cells to maintain the length of their telomere ends and escape replicative senescence; its regulatory role in metastatic events has also been proven. Many small molecule inhibitors of telomerase have been developed to date, however very few of them demonstrate significant antiproliferative or antitumor activity in vivo [ 15 ].…”