Compound called GRN163L blocks lung cancer

Sep 1 2005

Researchers at UT Southwestern Medical Center have found a compound that shows promise as a way to block the spread, or metastasis, of lung cancer.

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

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

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

Lung adenocarcinoma accounts for about 40 percent of lung cancers. Its rate is increasing worldwide, Dr. Shay said, and survival rates are poor because the disease metastasizes, usually by the time treatment begins in most cases.

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

GRN163L specifically matches a stretch of DNA at the end of the chromosome, a segment called the telomere. Normally, as cells divide and age, telomeres become shorter and shorter. When they reach a certain 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 telomerase is active in about 85 percent to 90 percent of tumors and in only a few noncancerous cells.

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

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

The researchers injected human lung tumor cells into the tails of mice and found that GRN163L blocked the development of metastatic tumors over several months. The higher the dose, the fewer tumors there were.

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

The research was partly responsible for getting the drug into clinical trials, where it will soon be tested on humans, Dr. Shay said. The trials, recently approved by the Food and Drug Administration, are at 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 GRN163L with other drugs and with radiation and therapy to see how it interacts with these other cancer treatments.

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

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