Is telomerase a viable target in cancer?

Abstract

The ideal cancer treatment would specifically target cancer cells yet have minimal or no adverse effects on normal somatic cells. Telomerase, the ribonucleoprotein reverse transcriptase that maintains the ends of human chromosome, is an attractive cancer therapeutic target for exactly this reason [1]. Telomerase is expressed in more than 85% of cancer cells, making it a nearly universal cancer marker, while the majority of normal somatic cells are telomerase negative. Telomerase activity confers limitless replicative potential to cancer cells, a hallmark of cancer which must be attained for the continued growth that characterizes almost all advanced neoplasms [2]. In this review we will summarize the role of telomeres and telomerase in cancer cells, and how properties of telomerase are being exploited to create targeted cancer therapies including telomerase inhibitors, telomerase-targeted immunotherapies and telomerase-driven virotherapies. A frank and balanced assessment of the current state of telomerase inhibitors with caveats and potential limitations will be included.

Fig. 1

Comparison of telomere lengths to cell divisions: human embryonic stem cells (ES) and perhaps induced pluripotent stem cells (iPS) have robust telomerase activity and may completely maintain telomere lengths. Somatic stem cells/progenitors that transiently express telomerase or only express moderate amounts of telomerase partially, but not completely, maintain telomeres. With increased age and cell divisions, telomeres continue to shorten in these cells. Normal somatic cells which do not express telomerase have the greatest rate of telomere shortening with each cell division. Cancer cells which reactivate or upregulate telomerase fully maintain telomeres but generally at greatly reduced lengths.

Fig. 2

Comparisons of chemotherapy alone to combining chemotherapy with a telomerase inhibitor. Due to some toxicities in combining therapies in phase I clinical trials, a phase II trial is in progress using the telomerase inhibitor, Imetelstat, in a maintenance setting following standard chemotherapy.