Molecular biologists aren’t a particularly grumpy lot, but they are grumbling these days that corporate interests – particularly those of the California-based Geron Corp. – may be stifling development of a promising new class of anti-cancer drugs called telomerase inhibitors.
Telomerase is a weird enzyme – part protein (called hTERT), part RNA (hTR). Its job is to restore a tiny bit of DNA at the ends of chromosomes.As normal cells divide over the course of a lifetime, these tiny bits of DNA, called telomeres (prounounced TEE-low-mears), gradually get shorter and shorter until they virtually disappear. Without telomeres, the cell can no longer divide, and therefore dies.
Unlike normal cells, cancer cells have figured out a way to keep making telomerase so that telomeres are kept intact. The obvious implication is that blocking telomerase with drugs should destroy cancer cells – and indeed it does, at least in the lab.
The grumbling – by some of molecular biology’s biggest superstars – is unusually bitter because 90 percent of human cancers show over-activity of telomerase, suggesting that they would be vulnerable to anti-telomerase drugs.
At telomere meetings, it’s “common for people to sit around and tell Geron horror stories,” says Elizabeth Blackburn, professor of biochemistry and biophysics at the University of California, San Francisco School of Medicine. The co-discoverer, in 1985, of telomerase, Blackburn consulted briefly with Geron in the past but stopped that arrangement, citing potential conflict of interest. As a university employee, she is listed as a co-inventor of telomerase inhibition technology. She no longer has ties to Geron.
Carol Greider, the other co-discoverer of telomerase and a professor of molecular biology and genetics at the Johns Hopkins University School of Medicine, says that the legal agreements Geron writes to share materials with others “are often onerous,” she says, adding, “I have decided not to try to get material from them, knowing it would be difficult.”
Robert Weinberg, a professor of biology at the Massachusetts Institute of Technology and a member of the MIT-affiliated Whitehead Institute, is even more blunt. “No one in this country has had the temerity to move into this field – they didn’t want to risk the ligitation,” he says. “All this is a shame because telomerase is an extremely attractive target for anti-tumor therapy and Geron, by squatting on its patent estate, has really blocked other people from attempting to develop possible useful anti-tumor drugs.”
Not surprisingly, Geron strenuously disputes this. “Those statements are simply not true,” says Geron’s chief scientific officer, Calvin Harley. At a recent meeting in San Francisco and others over the last seven years, he says, “we have shown all our data. We’re highly collaborative. We have given our reagants [research materials] to hundreds of labs.”
And Nobel Laureate Tom Cech, president of the Howard Hughes Medical Institute and the co-discoverer, in 1997, of the protein portion of the telomerase enzyme, undertands that view. “I don’t see anything different in the way Geron is treating telomerase than the way any biotech company treats its intellectual property,” he says, adding that he has “no connection” to Geron except that the company has licensed patents on discoveries made by Cech and his group at the University of Colorado.
Unlike most enzymes, which consist entirely of protein, telomerase is a combination of a protein called reverse transcriptase, which copies RNA into DNA, and a chunk of RNA, one form of genetic material that can also act as an enzyme.
Years ago, Blackburn noticed that the DNA on the ends of chromosomes “was growing and shrinking, which was not what DNA was supposed to do,” as she notes. She hypothesized that a special kind of enzyme called a polymerase must be at work. (Polymerases help create new chains of DNA.)
She and her then-graduate student Carol Greider found the enzyme and named it telomerase. It is highly active in early fetal development, when cells are rapidly dividing. But from birth through adulthood, telomerase is made at low levels in normal cells and stored in a tiny structure called the nucleolus inside the nucleus. Just before a normal cell divides, telomerase moves to the nucleus where it restore telomeres to shrinking chromosomes.
In cancer cells, and normal cells that divide rapidly such as stem cells in the bone marrow and skin , telomerase goes back to its furious, fetal pace. As a drug target, this raises some concerns. Anti-telomerase drugs might harm some normal cells, though researchers say this is unlikely because tumor cells have shorter telomeres and therefore would be more susceptible than normal cells to anti-telomerase drugs. In addition, stem cells don’t divide often, and when they’re not dividing, they should not be impacted by the drugs.
Another concern is that, as cells “erode their telomeres, they may go into a state of genetic instability, which, ultimately, could fuel the emergence of resistance to telomerase and other anti-cancer therapies,” says Dr. Ron De Pinho, professor of medicine and genetics at the Dana-Farber Cancer Institute.
Despite such concerns and all the squabbling, telomerase research is chugging along. Studies on 20 different types of tumors in laboratory dishes and in at least 10 animal models show that blocking telomerase does indeed cause cells to die. (Internationally, Boehringer Ingelheim is also working on telomerase, though the company adds the “therapeutic benefit” from inhibitor drugs “remains an elusive target.”
Geron expects to start human trials later this year in patients with a kind of brain cancer called glioblastoma using a drug dubbed GRN163. This compound is a telomere-like bit of DNA that binds to the key region of the telomerase enzyme, blocking its action.
The GRN163 drug is not perfect, in part because it’s 10 times bigger than most drugs. (In general, the smaller the drug molecule, the more easily it gets into cells.) But so far, says Harley of Geron, GRN163 has shown “no significant toxicity.”
Geron is also conducting a clinical trial of a telomerase vaccine in 20 men with prostate cancer with researchers from Duke University.
Unlike conventional vaccines, this one is designed to treat, not prevent, disease. The Geron vaccine is made individually for each patient, using the patient’s own immune cells, which are removed from the bloodstream and coaxed to display tiny pieces of the telomerase molecule, like little flags, on their surfaces. These cells are then re-injected in hopes of triggering a widespread immune response to cells carrying telomerase “flags.”
Other ideas are in the pipeline, including using detection tests for telomerase to diagnose cancer from blood samples, making “toxic telomeres” to destroy cancer cells, using viruses controlled by telomerase regulators to kill tumor cells, and seeing whether newly-discovered proteins that regulate the binding of telomeres to the ends of chromosomes might also be drug targets.
All this will, of course, take time. But it may also take tinkering with the delicate balance of corporate interests and public health.
As Tyler Jacks, director of the Center for Cancer Research at the MIT puts it, “There is a desperate need for more specific and more effective drugs for treating cancer. It would be extremely unfortunate if, due to intellectual property considerations, a very promising cancer target were not pursued as vigorously and as broadly as possible.”