Journal Article

Telomerase and cancer therapeutics

Harley, Calvin B.

2008

Overview

Key Points Telomerase is an important drug target for cancer. It is expressed in most tumours from virtually all types of cancers and is required for long-term maintenance of telomeres, which in turn is crucial for the long-term survival of tumour cells. Telomerase is a relatively specific cancer target as normal body cells express little or no telomerase for most of their lifespan and generally have longer telomeres than those in tumour cells. Two major approaches to killing telomerase-positive tumour cells are in clinical trials. A direct telomerase inhibitor, GRN163L, is in trials in chronic lymphocytic leukaemia, multiple myeloma, solid tumours and non-small-cell lung cancer. Several therapeutic vaccines directed against the crucial telomerase protein TERT are in or have completed trials in leukaemia and renal, prostate, lung, skin, pancreatic and breast cancer. Telomerase inhibitors can have fast-acting single-agent activity in certain cancers with short telomeres and rapid turnover, but this should not be the expectation in most patients. Putative cancer stem cells are telomerase-positive and thus telomerase inhibitors, in combination with effective tumour de-bulking agents, might help meet a major unmet need: durability of response. Telomerase vaccines offer the potential to stimulate the rapid killing of tumour cells by enhancing the activity of telomerase-specific cytotoxic (CD8 + ) and/or helper (CD4 + ) T cells. No significant toxicity to normal tissues has been seen in any of animal studies or clinical trials to date. Potential challenges in the clinical development of telomerase-based cancer therapies include selection of the best patient population, good pharmacodynamic or biological markers to assess early activity, and optimal dose and schedule for combination therapies. A specific telomerase inhibitor and several telomerase therapeutic vaccines are in clinical trials, and other telomerase-based therapies are in preclinical development. What are the advantages and disadvantages of these approaches and which cancer patients might benefit most? Telomerase is an attractive cancer target as it appears to be required in essentially all tumours for immortalization of a subset of cells, including cancer stem cells. Moreover, differences in telomerase expression, telomere length and cell kinetics between normal and tumour tissues suggest that targeting telomerase would be relatively safe. Clinical trials are ongoing with a potent and specific telomerase inhibitor, GRN163L, and with several versions of telomerase therapeutic vaccines. The prospect of adding telomerase-based therapies to the growing list of new anticancer products is promising, but what are the advantages and limitations of different approaches, and which patients are the most likely to respond?

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Antineoplastic Agents - pharmacology / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer cells / Cancer Research / Cancer Vaccines / Care and treatment / Clinical Trials as Topic / Enzyme Inhibitors - pharmacology / Gene Expression Regulation, Neoplastic / Genetic aspects / Humans / Immunotherapy - methods / Kinetics / Medical Oncology - methods / Methods / Models, Biological / Neoplasms - therapy / Oligonucleotides / Oligopeptides - pharmacology / Physiological aspects / review-article / Telomerase / Telomerase - antagonists & inhibitors / Telomerase - metabolism / Telomerase - physiology