VARI research: cancer, gigantism

September 21, 2009
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The Van Andel Research Institute in Grand Rapids recently released information about the results of several studies.

In July, VARI announced that its investigators have identified a gene that may serve as a new target in the treatment of an aggressive form of breast cancer. The study, published in Proceedings of the National Academy of Sciences U.S.A. in July, builds on work done in the 1980s by VARI Distinguished Scientific Fellow George Vande Woude at the National Cancer Institute. That work showed that the Met gene occurs at inappropriate levels in human tumors and that inappropriate Met signaling impacts the spread of cancer.

The VARI study, authored by Research Scientist Carrie Graveel and Research Technician Jack DeGroot, found Met present in most breast cancers and revealed the highest Met levels in a type of aggressive breast cancer known as basal.

“This very exciting work by the Van Andel Research Institute gives us a new target for treatment of patients with one of the worst types of breast cancer — basal breast cancer,” said Dr. Daniel D. Von Hoff, physician-in-chief of Van Andel Institute partner Translational Genomic Research Institute in Phoenix. “Since there are many new inhibitors of Met available for clinical trials, we now have a direct route for immediate applications of these important findings in the care of patients with this very aggressive form of breast cancer.”

Graveel noted that, in general, mortality rates for breast cancer are in decline. However, they remain high in women with aggressive cancers that don’t respond to traditional treatment.

In another cancer-related development, VARI researchers took an important step toward a new diagnostic tool for pancreatic cancer, a particularly deadly disease because it’s usually detected at a late stage.

The method focused on variations in carbohydrate structures that attach themselves to proteins in the bloodstream. While currently most diagnostic tests for pancreatic cancer rely on protein levels alone, identifying and studying alterations in the associated carbohydrate structures could reveal information about the cancer’s tendency to spread or its resistance to therapy, according to VARI Senior Scientific Investigator Brian Haab.

“These proteins can have carbohydrate structures attached to them that might be able to tell us not only if a patient has cancer, but also more about the cancer and how to treat it,” said Haab.

In fact, the protein that showed the most variation in carbohydrate structure has not been viewed as a target for diagnosing pancreatic cancer, said Tingting Yue, a Michigan State University graduate student at VARI and lead author. Measurement of the protein alone has not been a good predictor of the presence of cancer, Yue explained.

“We greatly need improved diagnostic tests to find tumors at the earliest possible stages to provide the most appropriate and effective treatment for pancreatic cancer patients and to improve their chances of recovery,” added Dr. Randall E. Brand, a University of Pittsburgh Medical Center professor and one of the study’s authors.

The study was published in the summer in the journal Molecular & Cellular Proteomics.

Cancer mortality was the focus of an analysis by Dr. Eric Kort, now a medical resident at DeVos Children’s Hospital in Grand Rapids. While a research scientist at VARI, Kort determined that cancer mortality rates have declined for younger patients more than was previously believed. That trend has been masked by the common use of composite age-adjusted rates to track cancer mortality.

Kort’s study, published in Cancer Research, examined cancer death rates by age groups. He found that of those born after 1925, all age groups have seen a decline in cancer mortality. The decline has been most pronounced in the youngest patients, at 25.9 percent per decade, while oldest groups have seen a 6.8 percent per decade decline.

These trends occurred even as the incidence of cancer has increased. Cancer is expected to pass heart disease as a cause of death next year simply because heart disease-related deaths are declining at a more rapid pace than cancer-related deaths.

“This study focuses on an aspect that has been overlooked in determining whether we’ve had a significant impact on cancer mortality,” said Vande Woude, an author of the study along with Kort and Dr. Nigel Paneth of MSU.

Also, a VARI researcher traveled to Borneo to find that some people are carriers of a genetic mutation that causes a form of gigantism even though they don’t have any symptoms. Dr. Bin Tean The, a distinguished scientific investigator, made the trip with staffers from the Department of Medicine at the Queen Elizabeth Hospital in Malaysia. They traveled to a mountainous village to collect blood samples in order to examine the genetic make-up of 31 members of an aboriginal family that included persons with acromegaly, a form of gigantism that often causes enlarged hands, feet and facial features.

The blood samples were studied by VARI Research Scientist Sok Kean Khoo, who was lead author of the study published in Endocrine-Related Cancer, and other researchers.

“Researchers had recently found a mutation in the AIP gene associated with acromegaly,” Teh said. “We found that several family members who didn’t have visible symptoms of acromegaly had this mutation, as well. This increases the importance of screening for families with cases of acromegaly since anyone could be a carrier. On one side of the family, at least two generations carried the gene before someone showed any symptoms.”

Acromegaly often results from a tumor on the pituitary gland. In later stages, it causes enlarged hands and feet, protruding brows and lower jaws, plus thick voices and slowed speech due to vocal cord swelling. Treatment entails removed of the tumor and gland, followed by lifelong hormone therapy. If untreated, heart or kidney failure may cause death.

While the incidence is estimated at 4,676 per million people, that does not include carriers who show no symptoms.

“The sooner we know how and why people are affected differently by this disease, the sooner we can help families who have it,” Teh said.

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