Although the field had barely begun less than a generation ago, telomere-telomerase biology was the main topic of symposia and discussion sessions at the annual meeting of the American Association of Cancer Research held in New Orleans this year.
Telomerase, an enzyme, is essential for the assembly of telomeres, repetitive DNA sequences on the ends of chromosomes that help to preserve their structural integrity. But Jerry W. Shay, Ph.D., a cell biologist in the Department of Internal Medicine at the University of Texas Southwestern Medical Center, Dallas, noted that, with certain exceptions (notably in the germ cells that give rise to eggs and sperm), telomerase makes itself scarce once the telomeres are complete.
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In brief, telomeres lacking access to telomerase shorten a little each time the cells that host them divide. Because cells seem to be allotted only so many divisions (the number varies with cell type), biologists believe that erosion is, in effect, a countdown mechanism. Its apparent purpose, in other words, is to put cells on notice when they have no more divisions coming to them. Such cells are senescent. They eventually succumb to apoptosis, programmed cell death.
Given that scenario, researchers were eager to re-examine an old observation: that many mammalian cancer cellsincluding those in humansdiffer from healthy ones in that they will continue to divide virtually forever in laboratory containers if properly housed and fed.
At issue here was the possibility of a link between telomerase and cancer cells propensity for immortality. But when the enzyme was discoveredin 1984 in Tetrahymena, a single-celled organismthe lack of an appropriate assay that was sufficiently sensitive and user-friendly stood in the way of rigorously testing that hypothesis.
It was not until 1994 that there was an assay with the needed attributes. Based on polymerase chain reaction technology, it came out of the laboratory headed by Shay and his colleague, Woodring Wright, M.D., Ph.D., and was soon used to demonstrate that mammalian cell lines in culture indeed owe their immortality to telomerase. Nor was this the entirety of the assays usefulness. Using it, first the Shay-Wright group and then others found high levels of telomerase in 85% to 90% of human cancers but either none of the enzyme or only negligible amounts in benign tumors and healthy tissue.
In 1996, the National Cancer Institute held a 2-day workshop, co-chaired by Shay, that focused on how telomerase assessments might be harnessed for screening and early detection and, by extension, perhaps for staging purposes and predicting treatment outcomes as well. At the time, there was considerable enthusiasm for the idea among the participants, although they also acknowledged that most of the data then available was preliminary and that some of it was conflicting.
Judging by Shays recent update at the American Association of Cancer Research meeting, "investigational" is still the word that best describes these applications, but there has been progress in readying some of them for the clinic.
Bladder Cancer
The applications may be particularly promising in bladder cancer, because a reliable way to screen for it is needed by those who, because of occupational exposures to certain chemicals or a history of smoking, are at high risk for the disease. Conventional cytology, as Shay put it, is of "marginal utility" in evaluating such people because it is better at picking up the cancer in its late stages when it is almost always fatal than earlier when it may be remediable.
By contrast he reported at the American Association of Cancer Research meeting that "results from a number of laboratories suggest that [measurements of the level of] telomerase activity can detect up to 70% of bladder cancers in stage one."
Meanwhile, it so happens that telomerase has two major components: 1) an RNA template for the repetitive DNA sequences of the telomeres and 2) reverse transcriptase, an enzyme that the template copies after it has positioned it at the tips of the chromosomes. There is, accordingly, great interest in developing cancer therapies that would cause the telomeres to shorten by taking aim at one component or the other or, perhaps, both.
Shays laboratory and many others are engaged in the effort, as is the Geron Corp., Menlo Park, Calif., a biotechnology firm. Among the ideas their researchers are pursuing are so-called antisense approaches that would inactivate the RNA template, and the introduction of a suicide gene into cells that express telomerase to cripple the reverse transcriptase protein. (Although the AIDS drug AZT would seem to be an obvious candidate for that assignment, results to date with it have been inconclusive because it slowed the growth of cells in culture but had no effect on their telomeres.)
Immunotherapy
And the list goes on. For example, because telomerase is found in such a high percentage of cancers and in so many different kinds, it is possible to imagine that immunotherapy directed against it could be beneficial. The work of Robert Vonderheide, M.D., D. Phil., of the Dana-Farber Cancer Institute, Boston, suggests that this just may be feasible.
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There can, of course, be no guarantees that any of the studies now under way will lead to drugs or other agents that can be given to patients to inhibit telomerase. On the other hand, suppose that at least some of the candidate interventions pan out. What can be expected of them? And how will they be used?
The short answer to these questions is that it is too soon to know. Still, Shay is betting that shutting off their telomerase will not immediately stop cancer cells in their tracks because the cells will not become senescent until their telomeres have shortened enough and that, even then, it will take them time to die. (The longer their telomeres are to start with, the longer their likely survival.)
For that reason, he predicts that telomerase blockers will be used as adjuncts to surgery, radiation, and chemotherapy. A study published in the April issue of Cancer Research, in fact, may be a hint of protocols to come. The work of Geron Corp. scientists and their collaborators found that telomerase deprivation made breast cancer cells maintained in culture more sensitive to doxorubicin, a drug widely used to treat the disease.
Reduce Relapse Risk
It is also possible, according to Shay, that telomerase inhibitors will be used after apparently successful standard treatment to nip possible micrometastases in the bud and thus reduce the risk of relapse. And down the road there may be yet another option: dual treatment with telomerase inhibitors and angiogenesis inhibitors.
"Were still doing basic research experiments on that one," said Shay. "But its a logical approach because angiogenesis inhibitors keep the tumor burden small but have no effect on the telomeres, and with telomerase inhibitors it is the reverse. If you can kill tumors off with apoptosis and keep them small in the meantime, it stands to reason that patients should be better off."
Drawbacks
Nevertheless, it is a rare therapy that does not have drawbacks, and telomerase blockers may be no exception. It is possible, for instance, that tumors will find a way to maintain their telomeres despite the use of telomerase blockers or that cells in the body that normally express telomerase, albeit intermittently, will be adversely affected. Moreover, such standard treatments as chemotherapy and radiation can both control cancer and cause it and some investigators worry that telomerase blockers may similarly turn out to be double-edged swords.
As things now stand, however, these risks are strictly theoretical and, even assuming they are real, no one knows how great they are. Barring some unforeseen development that precludes clinical trials, the fate of these drugs will be almost certainly be decided by how well or how poorly they fare when put to that test.
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