Therapy Analysis - Telomerase as a potential therapeutic target
A therapeutic target
Cancer cells generally have far shorter telomeres and a higher rate of division than normal somatic cells. This coupled with the practical absence of telomerase in normal somatic cells means telomerase could be a very attractive therapeutic target. There is the danger of stem cells being affected by such a therapy, but their lengthy telomeres could theoretically rescue them from the critical-length cycle-arrest system responsible for combating systemically treated cancerous and normal cells simultaneously. This way, drug resistance and the severe side-effects suffered by patients on current cancer treatments, particularly chemotherapy, could theoretically be avoided.
Therapeutically, antisense oligonucleotides, dominant negative mutant hTERT and reverse transcriptase inhibitors have been developed to various early stages. GRN-138098 was the first telomerase inhibitor recorded in Pharmaprojects in 1995, with no more under investigation until three years later, in 1998, when there was a steep increase in the number of agents reported to be under development. The number of inhibitors peaked at 12 agents in 2001, and since then there has been a steady decline up until the present day. As relatively cheap compound libraries and preclinical ex vivo studies were gradually ruled out, the majority of telomerase-inhibitors have had their development ceased. However, in 2006 both Pharmexa's GV-1001 and Geron's GRN-136L became the first telomerase-inhibitors to have reached Phase II trials, and in 2007, GV-1001 successfully entered Phase III clinical trials (Graph 1). Could these be emerging diamonds from amongst the rough of early leads?
Cancer Research Technology has three telomerase-inhibitor
compounds to its name (Graph 2), although only one of these
is still reported to be in active development, currently under
evaluation at the early preclinical stage. So far it has shown
efficacy as a single agent and with chemotherapeutics in
mouse xenografts.
Cosmo Bioscience is developing CB-10-01, a transgenic lymphocyte immunization vaccine against telomerase, which has reached Phase II trials. Leucocytes from the patient are treated ex vivo using gene therapy to recognize telomerase as an antigen, and are then returned to the patient. By doing this, it is hoped that cancer cells expressing telomerase will be targeted by the modified leucocytes, which will in turn illicit an immune response against them.
The Californian biotech outfit Geron currently has the largest telomerase-targeting drug portfolio past and present, with two drugs currently in preclinical trials, and one in Phase I/II. It has taken a different approach to Cosmo Pharmaceuticals, by synthesizing oligonucleotides (GRN163 and GRN163L) that target the template region of telomerase; these have demonstrated highly potent inhibitory activity in biochemical assays, various cellular systems and animal studies. GRN163L is currently in dose-escalation Phase I/II trials treating patients with chronic lymphocytic leukaemia as well as other types of cancer. Interim results have shown the agent to be well tolerated thus far.
Also under development by Geron is GRNVAC1, a telomeraseexpressing dendritic cell vaccine. The therapy involves ex vivo uptake of RNA encoding hTERT into autologous dendritic cells and their re-administration to the patient. The patient's T-cells are thus activated to kill telomerase-expressing cells. In Phase I/II trials, patients all showed robust cellular immune responses to telomerase based on tests assessing the generation of telomerase-specific cytotoxic CD8 and CD4 lymphocytes. Through Roche Diagnostics, Geron is also developing fluid-based telomerase detection tests for clinical in vitro diagnostics. The tests are based on telomerase detection assays that have already been commercialized by Geron for the research use-only market. The company hopes that the detection of telomerase may have significant clinical utility for cancer diagnosis, prognosis, monitoring and screening.
The only agent utilizing telomerase as a therapeutic target to have reached Phase III trials to date is Pharmexa's GV-1001, a peptide vaccine which has also been granted orphan drug designation in Europe. It activates T-cells of the immune system to recognise and kill telomerase-expressing cancer cells. In the trial (the TeloVac study), GV-1001 is being tested together in combination with the chemotherapy compounds gemcitabine hydrochloride and capecitabine in 1110 patients, including those with inoperable pancreatic cancer. Pancreatic cancer is currently mainly treated with chemotherapy, with little or no effect.
In May this year however, the agent suffered a serious setback, with enrollment into another Phase III trial (the PrimoVax study) being terminated. It was concluded that administering GV-1001, pre-gemcitabine chemotherapy, was no more efficacious than gemcitabine chemotherapy alone. The TeloVac study protocol of GV-1001 administered simultaneously with chemotherapy still continues, but doubt is now cast over the future of what until recently seemed such a promising therapy.
Cancer is not the only therapeutic area in which telomerasetargeting therapies may have potential. Research has shown that telomere loss in cytotoxic T-lymphocytes is accelerated in AIDS patients, and that this is a contributing factor to the loss of their anti-HIV activity over the course of infection. In addition, it has been shown that introduction of the telomerase gene into these T-cells increases their lifespan, enhancing the anti-HIV function of these cells.
Looking to counter this feature of HIV-infection, Geron and TA Therapeutics are developing TAT-0002, a small-molecule telomerase activator and modulator of telomere length for the treatment of AIDS and skin conditions. In a culture of TAT- 0002 and CD8 T-cells from HIV-positive donors, TAT-0002 reduced mean virus levels by 2.5 times for all donors compared to control, and in preclinical HIV studies, it stimulated T-cell proliferation and increased the cytolytic activity of CD8+ T-cells. Geron is currently planning on escalating development of TAT-0002 to Phase I/II trials.
