Researchers are tracking down genes and molecular markers linked to mesothelioma-a deadly asbestos-related cancer.

There are several misconceptions about mesothelioma.

For one thing, it is not lung cancer. It is a cancer of the two-layered membrane that covers and protects most of the body’s organs. That membrane, the mesothelium, is also called pericardium where it covers the heart, peritoneum where it surrounds most of the other abdominal organs, and pleura where it envelops the lungs, which is also where it most often turns cancerous.

Mesothelioma is not caused by smoking, as lung cancer so often is. Instead, mesothelioma is tied almost exclusively to the mineral asbestos. Of the 2,000 new cases of mesothelioma reported in the United States each year, 70 to 80 percent can be traced to tiny, airborne shards of asbestos, which in the past was used in the production of construction materials ranging from cement to shingles to siding, and was extensively used as insulation.

Mesothelioma also is not a disease of the past. Although protections against occupational asbestos exposure have been in place since the 1970s, asbestos-related cancers such as mesothelioma can take 30 to 50 years to show up, according to the Mesothelioma Applied Research Foundation.

Showing up generally means the cancer has been advancing for some time, says USC/Norris Comprehensive Cancer Center researcher Parkash Gill, M.D., professor of medicine at the Keck School of Medicine. “There is almost no such thing as early mesothelioma. It is not until later on that you get any symptoms.”

Which leads to the final misconception: Mesothelioma is not under control. In fact, more often than not, by the time there are symptoms, the mesothelial tumors are large and entrenched and pumping out fluid that fills the chest and compresses the lungs, resulting in organ failure and death. That is why the survival of mesothelioma patients is so poor: an average of 18 months after diagnosis, at best.

Gill and other USC/Norris researchers are working to change all that. With generous, ongoing funding from Jerry and Elizabeth Paul and the Mesothelioma Research Foundation of America, Gill and his group are tracking down genes and their protein products that play a role in mesothelioma and may be vulnerable to treatment.

Gill’s involvement in mesothelioma research arose naturally out of his ongoing interest in tumor blood-vessel growth and maturation. “The cell of origin in mesothelioma is a cousin of blood-vessel precursor cells,” he says. In addition, the fluid found in mesothelioma is the result of blood-vessel leakage. “It all fits together perfectly, from a research standpoint,” Gill says.

Gill’s lab has tracked down two new target genes in the fight against mesothelioma, both of which are linked to blood-vessel growth. “Both of these genes are highly expressed in mesothelioma, and both are found on the surface of the cell,” he says. “We’ve already identified inhibitors for both of them, and we’ve shown that when you turn these genes off, you stop the growth of the tumor. So they are both good targets for therapy.”

Another good target for therapy are the genes that produce a protein called vascular endothelial growth factor, or VEGF. Gill provided the first-ever evidence that VEGF—produced by a wide variety of tumor types—is used not only to promote the growth of blood vessels at the tumor site, but promotes growth of the tumor cells themselves.

In a recent study published in the International Journal of Cancer, he and his colleagues showed that VEGF is linked to the growth of mesothelioma tumors, which can be inhibited, in laboratory dishes, by treatment with a VEGF inhibitor. Such an inhibitor is already undergoing a Phase I clinical trial at the USC/Norris. In this trial, headed by Alexandra Levine, M.D., Distinguished Professor of Medicine and chief of hematology at the Keck School, a drug called Veglin is being employed against a variety of tumors that have been shown to produce VEGF.

“Mesothelioma is a very good disease on which to test this drug,” says Gill. “I expect it to have a direct effect on both tumor growth and production of fluid. That would really make a difference in the course of this disease.”

An even greater effect could be made on mesothelioma if it could be caught in its earliest stages before symptoms appear, says USC/Norris researcher Ite Laird-Offringa, Ph.D., assistant professor of surgery and biochemistry at the Keck School of Medicine. To do that, she says, you would need to have some sort of molecular marker that you could test for, much the way physicians now can test for prostate-specific antigen, or PSA, to detect prostate cancer in the early stages.

What she and her colleagues have found is that, in the case of mesothelioma, the best kind of molecular markers are those that are associated with changes in DNA, because DNA lends itself to manipulation. A protein such as PSA is a good marker only if there is enough of it produced by the tumor—and no such marker has yet been found for mesothelioma. DNA, on the other hand, can be artificially amplified so that a marker that is a mere whisper of a clue suddenly becomes apparent. But searching a cell’s entire genome for subtle genetic changes—mutations or deletions—would be almost impossible. The answer, says Laird-Offringa, is to look for a different kind of change—one that is easier to spot and analyze. One like DNA methylation, a form of gene silencing that is one of the major research strengths at USC/Norris.

In DNA methylation, a chemical cluster called a methyl group is physically stuck onto a strand of DNA, creating a genetic roadblock. “DNA methylation turns off genes that stop cells from turning cancerous,” says Laird-Offringa. “And it does so in identifiable patterns, creating profiles that differ and can be compared between tumors.

“In other words, if we look at the profiles, we should be able to tell what kind of cancer we are dealing with.”

Finding those patterns may be easier than looking for a DNA deletion or mutation—but it still requires significant effort. That is why Laird-Offringa and her husband, molecular biologist Peter Laird, Ph.D., are joined in their effort by surgeon Jeffrey Hagen, M.D., who collects mesothelial tissue samples, pathologist Michael Koss, M.D., who confirms whether the samples are indeed mesothelioma and marks their borders, and statistician Kimberly Siegmund, Ph.D., who analyzes the data derived from those samples.

With a dedicated research grant from the Mesothelioma Applied Research Foundation, this team has already looked at a series of 14 known DNA methylation markers, trying to determine whether any of them are indicative of mesothelioma—or of lung adenocarcinoma, a common form of lung cancer that can be difficult to distinguish from mesothelioma. Five of those 14 markers were informative in some way, says Laird-Offringa: One seemed to be a marker for adenocarcinoma, another was more common in mesothelioma and the other three allowed for discrimination between the two forms of cancer and the normal lung tissues.

“It was a small study,” says Laird-Offringa, “but it did show that it is possible to use methylation profiles to discriminate between different types of cancer. That’s a big step.” The next step is not only to find more markers, but to look at these methylation profiles in significant numbers of patients—and to see if they not only help in diagnosis, but in creating individual molecular profiles that can determine the likely course of the disease and even the patient’s response to treatment.

“We’re hoping to get to the point where, if a patient knows he or she has had asbestos exposure, we can test them, so that if they develop mesothelioma, it can be detected at an early stage,” says Laird-Offringa. “That’s the key to survival—detecting the cancer early enough that it can be taken out and the patient can be cured. That’s what is most important.”

by Lori Oliwenstein

Mastering Mesothelioma