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IU Simon Cancer Center researchers target telomeres to attack tumors

  

INDIANAPOLIS -- (May 5, 2009) -- Hoping to develop more effective long-term attacks on cancer, researchers at the Indiana University Melvin and Bren Simon Cancer Center are conducting the first human tests of a breast cancer drug regimen that includes a compound meant to force cancer cells to grow old and die.

The early stage clinical tests are an attempt to block a mechanism cancer cells use to avoid the aging process that affects most normal cells. If successful, the new therapy could enhance the effects of other cancer treatments.

“This is really a completely different way of trying to tackle the problem that hasn’t been tested in the clinic before,” Kathy Miller, M.D., associate professor of medicine and Sheila D. Ward Scholar at the Indiana University School of Medicine and medical oncologist at the IU Simon Cancer Center, said.

The clinical test is a good example of how positive results in basic science experiments can push a promising compound from the laboratory to the bedside -- a process known as “translational research.”

The new approach is based on research into telomeres, the caps that protect the ends of the 46 chromosomes in each cell that contain our genetic information. The telomeres, which some compare to the tips of shoelaces, help prevent genomic instability. Each time a cell divides, the telomeres shorten. When they become too short, losing their protective ability, it’s a signal to the cell to die, or to go into a state of permanently arrested growth called senescence.

Telomeres in cancer cells generally are shorter than those in normal cells. That offers a tempting target, except that cancer cells know a trick. Cancer cells produce an enzyme called telomerase, which provides maintenance services on the telomeres, preventing them from reaching the critically short stage that would set off the cell death signal.

So, researchers have figured, if you could block cancer cells from producing telomerase, you could make them easier to kill. But how to do that? Several approaches seemed possible, including one that Brittney-Shea Herbert, Ph.D., then a post-doctoral researcher, was working on 10 years ago at the University of Texas Southwest in Dallas. Her approach: Find a special type of chemical compound, called an oligonucleotide, that would block access to telomerase and prevent it from doing its job. She began working with a new compound, with the chemical name GRN163L, that had been developed by Geron Corp. of Menlo Park, Calif.

Dr. Herbert has continued to work with GRN163L -- now called imetelstat sodium -- in the laboratory since coming in 2003 to the IU School of Medicine, where she is an assistant professor of medical and molecular genetics and a researcher with the IU Simon Cancer Center. She has published work showing that imetelstat disrupts telomere maintenance, in the process suppressing both tumor growth and metastasis – the appearance of tumors in other tissues. Another study found that telomere damage in breast cancer cells treated with the compound caused the cells to be more susceptible to radiation treatment. Furthermore, she has shown that imetelstat can restore the sensitivity of Herceptin-resistant breast cancer cell lines in the laboratory.

“What’s interesting about GRN163L is that it can get into almost any cancer cell type, including drug resistant cancer cells. That’s been a problem: A lot of agents cannot be taken up into drug resistant cells. This telomerase inhibitor can be taken up in any cell type – you can target those cells. So that’s why we hope this will be great for reducing recurrence and metastasis,” Dr. Herbert said.

Such results have made imetelstat an attractive compound to test in conjunction with other anti-cancer drugs, which is what brought Drs. Miller and Herbert together. They are testing imetelstat with the drugs Taxol and Avastin, initially to determine the appropriate dose of imetelstat, test whether the three drugs are safe to give in combination, and to determine whether there are side effects that must be dealt with.

Assuming the first phase goes well a second phase of testing will begin more formal evaluation of how well the combination therapy works.

Dr. Miller’s research has shown that Taxol and Avastin are more effective in combination than Taxol alone, shrinking tumors in about twice as many women and providing such benefits more than twice as long. The therapy doesn’t cure metastatic disease, though. Eventually the tumors become resistant to the drugs and other treatments are necessary.

If, as expected, imetelstat doesn’t raise side effects issues, and “if it makes the cells more sensitive to the effects of the Taxol and Avastin, and allows the benefits of that therapy to continue for a much longer period of time, that would be a big benefit for those ladies with metastatic disease. It would also then give us the support for looking at this agent even earlier in the course of disease,” Dr. Miller said.

Dr. Herbert’s research indicated that imetelstat can reduce metastatic spread of cancer, though it’s not yet clear what the mechanism is. But, as Dr. Miller points out, for patients that will be a distinction with little difference.

“Whether it actually prevents the cells from spreading or they spread but can’t grow to make clinically apparent tumors we don’t know, but I can tell you my patients don’t care,” she said.