Even the most commonly mutated tumor suppressor genes, such as p53 and Rb, malfunction in only about half of all tumor types. However, excess telomerase appears in all major cancers. So why don't more pharmaceutical strategies exist to block the enzyme that, in excess, dictates cells to divide ad infinitum?
The answer may be twofold, Serge Lichtsteiner, a researcher at Menlo Park, Calif.-based Geron Corp., reported during an interview following his presentation at a recent New York Academy of Sciences cancer meeting. Telomerase has emerged as a viable anticancer target relatively recently, so researchers know less about the basic biology behind the enzyme's activity.1 Also, many questions remain about antisense molecules, currently the leading technique for turning off telomerase.2
The ability to switch off that enzyme seems tantalizing due to telomerase's key role in cell division. Telomerase rebuilds telomeres, the chromosomal tips that dictate the number of times a cell can divide. Those tips normally shorten after each cycle, until they become so small that they can function no longer and the cell enters senescence. Overabundant telomerase prevents senescence by rebuilding those tips.
While scientists grasp telomerase's basic role in cell division, they lack knowledge of its regulation. That, in turn, limits ways to target the enzyme, Lichtsteiner explains. For example, developing a small molecule that inhibits telomerase-related kinases seems sound--but there's a catch: "We don't know which kinase actually modifies telomerase," Lichtsteiner explains. "We need to understand better ... how telomerase is regulated in vivo, because that might point out a new target that ultimately will lead to specific inhibition of telomerase."
New knowledge--and potential new ways to targeting telomerase--are emerging, confirms Jerry W. Shay, a professor of cell biology and neuroscience at the University of Texas (UT) Southwestern Medical Center at Dallas. "There are other approaches for the development of telomere/telomerase therapeutics and it may be in the best scenario to attack telomere biology from a variety of different angles," Shay writes in response to an E-mail query. Recent discoveries, like a cellular gene on chromosome 3 that Shay suspects represses telomerase activity may provide one alternatives.3 Other basic observations may lead to different therapeutic strategies. "For example, alterations in proteins that bind telomeres are known to affect telomere length regulation," Shay writes. "In addition, one can target other components of telomerase besides the functional [template] RNA component." Shay points to hTERT, the catalytic protein component of telomerase, as an example. "We have made a mutation in one of the conserved reverse transcriptase domains of hTERT and when this is introduced into tumor cells with telomerase, this mutant version of hTERT acts as a dominant/negative and inhibits telomerase, resulting in telomere shortening."
Still, antisense approaches remain at the forefront. Antisense molecules could degrade telomerase in vivo or block the enzyme's production by binding to the biochemical template that gives rise to it. Antisense proponents tout antisense's specificity. But Lichtsteiner wonders if antisense will be specific enough. "The risk here is that if the active domain of the enzyme is very similar to a polymerase that is necessary for the function of normal cells ... a lot of compounds that are going to mess with [not just] telomerase, but also with other enzymes." Specificity might be increased by combining antisense with gene therapy delivery, he adds.
Shay notes that the most potent antisense approach at present is 2'-O-methyl-RNA (2'-O-meRNA) or an oligonucleotide that exerts sequence-specific effects in cell culture and animals. When delivered with cationic lipids, the oligo selectively inhibited telomerase upon transfection of human prostate tumor-derived DU145 cells by binding to cells' telomerase-producing template, Shay reports. Although Arnold J. Levine, president of Rockefeller University, calls telomerase a "promising" target, he remains cautious about inhibiting it with antisense molecules. "We don't understand the mechanism, and without the mechanism, it's hard to comment that this is going to be terrifically useful."