Telomeres are protective caps at the ends of human chromosomes. Telomeres shorten with each successive 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 present in very low levels or is almost undetectable in normal cells. Because
telomerase plays a pivotal role in
cancer cell growth it may serve as an ideal target for anticancer
therapeutics. Inhibition of
telomerase may lead to a decrease of telomere length resulting in cell senescence and apoptosis in
telomerase positive
tumors. Several strategies of
telomerase inhibition are reviewed, including small molecule inhibitors,
antisense oligonucleotides,
immunotherapies and gene
therapies, targeting the hTERT or the
ribonucleoprotein 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
therapeutics are the
antisense oligonucleotide inhibitor GRN163L and
immunotherapies 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
therapeutics have shown to be more effective when used in combination with standard
therapies, resulting in concomitant telomere shortening and
tumor mass shrinkage, as well as preventing
tumor relapse and resistance to single agent
therapy.