UNMC receives grant to better diagnose lymphomas

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Wing "John" Chan, M.D., left, talks with Guimei Zhou, M.D., and Javeed Iqbal, Ph.D., about results from laboratory experiments.
UNMC has received a nearly $9 million grant from the National Cancer Institute (NCI) to better diagnose lymphomas through microarray technology -- one of the largest research grants in the history of UNMC. The technology uses a specialized Diagnostic Lymphdx Array "chip" -- tiny array probes - to study cancerous genes.

The technology helps researchers profile or "decode" genes to find what is causing the cancer. In the past five to six years, the team has discovered so-called "signatures" that appear to define different types of lymphomas, said Wing "John" Chan, M.D., professor of pathology and co-director of the Center for Lymphoma and Leukemia Research at UNMC.

Dr. Chan is principal investigator of the five-year grant, which researchers hope will ultimately increase the chance of survival of lymphoma patients.

Besides UNMC, the study also is being conducted at the NCI and in New York, Arizona, Ohio, Canada, Spain, the United Kingdom, Germany and Norway. The group was funded in 1999 for a $4.2 million grant to launch the project.

Who is involved?
The following UNMC researchers are involved in the project: Warren Sanger, Ph.D., Bhavana Dave, Ph.D., James Eudy, Ph.D., Kai Fu, M.D., Timothy Greiner, M.D., James Lynch, Ph.D., Julie Vose, M.D., and Dennis Weisenburger, M.D.

"We hope microarray technology will lead to a better understanding of the basic mechanisms in lymphoma and hopefully provide a more effective way to determine the diagnosis and prognosis of patients," Dr. Chan said. "But we're not stopping at diagnosis and prognosis. Predicting what's going to happen to a patient doesn't help the patient a whole lot. We hope to find targets we can use to develop therapy that may lead to better therapy and increased chance of survival."

Researchers are making progress in giving physicians the ability to tailor cancer treatment for patients. Advances in deoxyribonucleic acid (DNA) microarray technology are enabling researchers and physicians to study the expression of genes, or how they behave.

Physicians and scientists expect this information will someday predict how aggressive a patient's cancer is and whether the cancer is resistant to chemotherapy. Microarray technology may replace many of the current ancillary diagnostic tests and may help devise better, more targeted treatments.

Lymphomas -- cancers that begin by the malignant transformation of a lymphocyte in the immune system -- are divided into two major categories: Hodgkin's lymphoma and non-Hodgkin's lymphoma. Though the death rates from many cancers have been dropping each year, non-Hodgkin's lymphoma is increasing 1.4 percent a year. About 62,000 people are diagnosed each year in the United States.

DNA microarray technology allows researchers to determine which genes are active within cells. Microarrays, also known as gene chips, are glass slides that have been coated with thousands of spots of DNA, each representing a different gene. When a gene is active in a cell, it produces RNA copies known as transcripts.

To measure the activity of genes, researchers use the RNA transcripts to make a fluorescent gene probe. When these gene probes are allowed to bind to their corresponding DNA spot on the chip, those spots on the chip light up. Scientists use the pattern and intensity of light emitted to determine the activity of each of the chip's thousands of genes.

On the forefront
Though a number of groups are studying similar application of microarray technology on other cancers, UNMC may be the largest funded group working on lymphoma, said Wing "John" Chan, M.D., professor of pathology and co-director of the Center for Lymphoma and Leukemia Research at UNMC.

Dr. Chan is principal investigator of a nearly $9 million grant awarded by the U.S. National Cancer Institute (NCI).

"We probably have the largest consortium in the molecular profiling of lymphoma," Dr. Chan said. "You have to have the patients and clinical resources to do effective microarray experiments. We have a long-term interest in lymphoma and have built-up a very large patient database and collection of clinical and pathologic information from mostly America and Europe."

Dr. Chan said there are a lot of centers that see people for lymphoma, but not everyone has access to laboratories, resources and collection of data and tissue.

"Since Dr. (James) Armitage and Dr. (Dennis) Weisenburger arrived in 1982, we've been building resources to study lymphoma. That is our lifetime interest," Dr. Chan said. "We hope our research efforts will improve the survival and quality of life of patients. The diagnostics and prognostics are just one part of the project."

Work with DNA microarrays began about 10 years ago and has been applied to the investigation of cancers for about the past six years, Dr. Chan said.

The lymphoma study consortium formed about six years ago, as well. Since then, it has studied 700 to 800 patient tumor cases and will study 2,400 cases in the new study. Microarray technology appears to be a very promising way of studying lymphoma, Dr. Chan said. "When you have a certain code, you know what that means," he said. "We already have the code for some lymphomas, but not for everything. Genetic profiling of tumors will offer extra power in predicting which patients will do well and which will do poorly. This more precise diagnosis should help in the future in more accurately guiding a patient's treatment decisions."

For example, he said, about 20 percent of patients with follicular lymphoma have a more aggressive form of the disease and shorter survival. "This group of patients probably have to be treated differently with more aggressive chemotherapy or transplantation," Dr. Chan said.

To date, only limited amounts of targets have been identified, he said. Most cancer treatments such as chemotherapy are applied broadly and are toxic.

"We hope to develop a more targeted therapy," he said. "For example, certain genes are abnormal and we know the function, then we'll target that function."

Such a target has been identified for chronic myelogenous leukemia (CML). A drug then was developed that targets the abnormal tyrosine kinase - a protein expressed in CML. "Many patients can go into remission with minimal side effects," Dr. Chan said. "We hope the same model can be used in all sorts of cancer. You have to know what is abnormal, then you have to develop a drug that can act on that abnormality. We hope we will find similar targets to develop specific therapy, not something that kills a lot of normal cells, like chemotherapy."

Dr. Chan said the team has diagnostic and prognostic signatures for about 85 percent of all the lymphomas, which include diffuse large B-cell, follicular, mantle cell, and Burkitt's. The next phase of work will further validate and refine the prognosticators to make sure they are accurate and useful in clinical practice.

"If the project is successful, it would indicate that we could predict the evolution of the patients' disease more precisely and therefore we could select a better therapy for them," said Elias Campo, principal investigator of the study at the University of Barcelona. "This could be one of the first translations to clinical practice of the new knowledge generated after the sequencing of the whole human genome.

"I think one of the most interesting aspects of this project is the collaborative effort among different institutions from different countries," Dr. Campo said. "This is a broad international task force. The power of the consortium, in addition to the high level of expertise of all contributors, is that we can gather a tremendous amount of information in a relatively short period of time and from different geographic areas."

Dr. Chan said physicians might be able to apply the research findings in the clinical setting in five to 10 years.

"Dr. Chan's grant is focused on finding genes that are abnormal in different types of lymphomas," said Julie M. Vose, M.D., Neumann M. and Mildred E. Harris Professor, and chief of the section of hematology/oncology at UNMC. "This could mean that we could more individually tailor-make the treatment that would be more beneficial for patients by using specific chemotherapy or monoclonal antibodies which work against these specific genes. This hopefully would help to improve the patient's chances for a long-term remission and cure of their lymphoma."

For more information on lymphoma, see the Leukemia and Lymphoma Society's Web site at www.lls.org.