David J. Argyle, BVMS, PhD, DECVIM-CA (Oncology), MRCVS
To 'think outside of the box' is a term that has become a cliché in management circles but is a phrase that could so easily be applied to cancer biologists. As we further explore the uncharted waters and murky depths of the cancer cell, new theories, pathways and mechanisms are reaching us from all walks of biology and from all species. It has taken nearly 50 years for biological concepts to come together to establish the clear mechanistic links between ageing pathways and cancer biology. The original work by Hayflick and Moorhead demonstrated natural replicative senescence in cells over 40 years ago and was later supported by seminal experiments demonstrating progressive telomeric attrition with every cell division. It is now well established that the majority of cancer cells overcome telomeric attrition by reactivation of an enzyme called telomerase, the prize for the cancer cell being immortality. As telomerase is now regarded as a near universal marker of malignancy, this lecture will discuss some of the implications of this enzyme in developing novel cancer therapies.
If one charts the history of cancer discovery over the past 50 years, it would be easy to become bewildered with the myriad of descriptions of ever more complex cellular pathways. However, in real terms we can distil these into seven basic traits that a cell must acquire to become a cancer cell. These are: insensitivity to anti-growth or proliferation signals, self sufficiency of growth signals, maintenance of a blood supply, escape from apoptosis, ability to invade and metastasize, escape from immunity and immortality. Immortality for 95% of cancers is achieved through the reactivation of the enzyme telomerase which serves to maintain chromosomal ends as the cells divide.
Telomerase is now regarded as a near universal tumour antigen and thus represents both a target for therapy and a potential diagnostic tool. In telomerase positive tumours, inhibition of telomerase leads to cell death and regression of cancerous lesions in experimental models. Numerous anti-telomerase therapies have been suggested and are at various stages of clinical development in human medicine. Further, various strategies are being developed in veterinary species, particularly in the dog. The dog is particularly important because mouse telomere and telomerase biology is very different from humans, thus the dog represents potentially a more valuable pre-clinical model.
There is little doubt that in veterinary medicine we are faced with an increasing population of ageing dogs and cats as we reap the rewards of successful vaccination campaigns. However, this comes at a price as we are also faced with an increasing incidence of age-related diseases such as cancer and arthritis. Conventional cancer therapies (e.g., chemotherapy) are crude at best and there is little doubt in the authors mind that we need to focus on developing novel targeted therapies that hit particular pathways in cancer that are absent from normal tissues. Telomerase would seem to be the obvious target as it is present in the majority of cancers encountered in canine and feline practice. So what is the hold up?
Telomerase is an exciting target. It is near universally expressed in the majority of cancers, it is immunogenic and it is required for cancer cell survival. However, for those of us that have worked with this enzyme for a number of years, it also represents a complex target. Although transcriptionally targeted vectors and RNA interference represent an advance in therapeutic development, delivery in vivo remains the single largest obstacle to clinical development. Further, the use of transcriptionally targeted replication competent viruses, although efficient, would require a rigorous safety profile. It is also naïve to consider that telomerase inhibition or targeting alone would be sufficient as a cancer therapeutic. Despite this, these are not insurmountable problems and anti-telomerase therapies are set to become prominent players in cancer therapy. We have recently developed a highly efficient RNAi molecule that specifically targets canine telomerase and are currently developing a strategy for delivering this in vivo6. Further, combining this form of therapy with targeting tyrosine kinase pathways seems to be synergistic in several model systems.