Novel anticancer therapeutics targeting telomerase

Telomeres are protective caps at the ends of human chromosom es. Telomeres shorten with each succes- sive cell division in normal human cells whereas, in tumors, they are continuously elongated by human telomerase reverse transcriptase (hTERT). Telomerase is overexpressed in 80-95% of cancers and is pres- ent in very low levels or is almost undetectable in normal cells. Because telomerase plays a pivotal role in cancer cell growt h it may serve as an ideal target for anticancer therapeutics. Inhibition of telomerase may lead to a decrease of telomere length resulting in cell senescenc e and apoptosis in telomerase posi- tive tumors. Several strategies of telomerase inhibition are reviewed, including small molecule inhibitors, antisense oligonucleotides, immunother apies and gene therapies, targeting the hTERT or the ribonucleo- protein subunit hTER. G-quadruplex stabilizers, tankyrase and HSP90 inhibitors targeting telomere and telomerase assembly, and T-oligo approach are also covered. Based on this review, the most promising current telomerase targeting therapeutic s are the antisense oligonucleotide inhibitor GRN163L and immunother apies that use dendritic cells (GRVAC1), hTERT peptide (GV1001) or cryptic peptides (Vx- 001). Most of these agents have entered phase I and II clinical trials in patients with various tumors, and have shown good response rates as evidenced by a reduction in tumor cell growth, increased overall disease survival, disease stabilization in advanced staged tumors and complete/partial responses. Most therapeutic s have shown to be more effective when used in combination with standard therapies, result- ing in concomitant telome re shortening and tumor mass shrinkage, as well as preventing tumor relapse and resistance to single agent therapy.