Table 2.
Therapies directed at telomerase or telomeres
| Mechanism of action | Example | Prostate cancer relevance | Refs |
|---|---|---|---|
| Telomerase inhibition with small molecules | Imetelstat is a lipid-conjugated 13-mer oligonucleotide that functions as a small molecular telomerase inhibitor by binding to the RNA template, TERC, and disrupts telomerase activity. | Clinical trials in breast and lung cancers have not been successful. No clinical trials of telomerase small molecule inhibitors in prostate cancer exist, but preclinical studies of prostate cancer cell lines show that imetelstat causes telomere shortening in tumour-initiating cells. | 167,169 |
| Telomerase vaccine | GV1001 is a 16-mer peptide vaccine containing a TERT amino acid sequence used to elicit immune responses against cells with telomerase activity. | No studies have investigated the use of GV1001 in prostate cancer to date. In pancreatic cancer, clinical trials of the vaccine have shown the agent to be immunogenic and well tolerated in patients; however, GV1001 was not efficacious as a single agent or in combination therapies. | 173,204 |
| TERT-regulated oncolytic virus | Telomelysin is a replication-selective adenovirus engineered to express the essential viral E1 replication genes under the control of the TERT promoter. | Telomelysin was effective in a LNCaP tumour model in nude mice. Completed phase I trials of telomelysin in various solid tumours (not including prostate cancer) have indicated no severe adverse effects following administration, but patient tumour response was limited. | 172,205 |
| Telomerase inhibition through AR down regulation | AR inhibitor bicalutamide and methaneseleninic acid downregulate AR protein level | AR inhibition using methaneseleninic acid in combination with bicalutamide decreased TERT expression and increased apoptosis in prostate cancer cells. | 136 |
| Telomere deprotection | G-Quadruplex stabilizers and telomestatin | No G-quadruplex stabilizers that specifically target telomeres have advanced to clinical trials. Quarfloxin, which has advanced to clinical trials, does not interact with telomeres, but with ribosomal DNA G-quadruplexes in the nucleolus. Telomestatin disrupts the interaction of shelterin protein TRF2 with telomeres in glioma stem cells, but the effects in prostate cancer have not been investigated. Prostate cancer mouse models responded to treatment with TMPyP4 and RHPS4. | 206–210 |
| Telomere dysfunction through AR inhibition | AR inhibitor (for example, bicalutamide or enzalutamide) and ATM inhibitor (KU-60019) | In prostate cancer cell culture studies, AR inhibition resulted in telomere dysfunction. ATM inhibition blocked cell cycle checkpoint arrest and prevented the repair of damaged telomeres caused by AR inhibition, promoting cell death. | 193 |
AR, androgen receptor; TERC, telomerase RNA component; TERT, telomerase reverse transcriptase.