Researchers Find Drug That Blocks Spread Of Lung Cancer In Mice

The researchers found that the compound blocks an enzyme that isknown to keep cells immortal and that is implicated in almost all humancancers. From results in mice, they determined that the compound,called GRN163L, also works rapidly and in doses that would bereasonable for therapy. It may be particularly useful after surgery orin combination with chemotherapy or radiotherapy to prevent residualcancer cells from spreading.

"We showed for the first time that this drug can work inanimals," said Dr. Jerry Shay, professor of cell biology at UTSouthwestern and senior author of the study, which appears in theSeptember issue of the journal Cancer Research.

Lung cancer is the leading cause of cancer death, killing morepeople than breast cancer, prostate cancer and colon cancer combined,according to the American Cancer Society.

Lung adenocarcinoma accounts for about 40 percent of lungcancers. Its rate is increasing worldwide, Dr. Shay said, and survivalrates are poor because the disease metastasizes, usually by the timetreatment begins in most cases.

The researchers designed, synthesized and tested GRN163L, whichconsists of 13 nucleotides, the units that make up DNA, plus a fattysection that improves the rate at which cells take it in.

GRN163L specifically matches a stretch of DNA at the end ofthe chromosome, a segment called the telomere. Normally, as cellsdivide and age, telomeres become shorter and shorter. When they reach acertain length, the cells stop dividing.

But the telomeres in cancerous cells stay the same length,thanks to an enzyme called telomerase. The gene that creates telomeraseis active in about 85 percent to 90 percent of tumors and in only a fewnoncancerous cells.

"Telomerase is the immortalizing gene," said Dr. Shay.

Telomerase doesn't cause cancer, but it allows the cancer cellsto keep dividing. It's almost a universal target for fighting cancer,Dr. Shay said, and its specificity is what makes it attractive forattack. Telomerase works by binding to DNA and, with a protein section,keeping the chromosome from getting shorter. GRN163L apparentlyprevents telomerase from binding.

The researchers injected human lung tumor cells into the tailsof mice and found that GRN163L blocked the development of metastatictumors over several months. The higher the dose, the fewer tumors therewere.

"That suggests that this drug prevented the lung metastasis,"Dr. Shay said, noting that the reactions took place at doses that wouldbe considered reasonable for treatment. The compound might not beeffective, however, in someone in whom metastasis has already begun, hesaid.

The research was partly responsible for getting the drug intoclinical trials, where it will soon be tested on humans, Dr. Shay said.The trials, recently approved by the Food and Drug Administration, areat an early stage, in which the drug is simply being tested for safety.

"We will be surprised if we see any toxicity," he said.

Future experiments on animals will involve combining GRN163Lwith other drugs and with radiation and therapy to see how it interactswith these other cancer treatments.

"What we're really interested in is getting this noveltherapeutic to work, to minimize the suffering and pain that peoplehave with cancer therapy," Dr. Shay said.

Other UT Southwestern researchers involved in the study wereDrs. Gunnur Dikmen and Ginelle Gellert, former postdoctoral researchersin cell biology, Dr. Shalmica Jackson, postdoctoral researcher in cellbiology, and Dr. Woodring Wright, professor of cell biology.Researchers from the Geron Corp. also participated.

The work was supported in part bythe National Cancer Institute, Geron Corp., Tubitak and the TurkeyEducation Foundation in Turkey.

This news release is available on our World Wide Web home page athttp://www.utsouthwestern.edu/home/news/index.html

To automatically receive news releases from UT Southwestern via e-mail,subscribe at www.utsouthwestern.edu/receivenews