MEDICAL BULLETIN

Progressive environment will benefit cancer patients

Colon cancer research is focus for some of building’s lab space

“The opportunities created by having the new space are enormous,” says Sanford Markowitz, M.D., Ph.D., pictured here in the lobby of the new Wolstein Research Building.

Sanford Markowitz, M.D., Ph.D., has a compelling reason to carry on his daily fight against colon cancer: his patients.

Patients who participate in clinical research display “nobility,” said the Frances Wragg Ingalls Professor of Cancer Genetics in the division of hematology/oncology of the Department of Medicine, and he is not about to disappoint them.

With the opening of the Iris S. and Bert L. Wolstein Research Building on the Case campus, Dr. Markowitz said collaboration and interaction with other scientists will foster a progressive research environment.

“The most important impact that the move to the Wolstein Building is going to have is the opportunity to bring different labs from the Case Comprehensive Cancer Center and put them juxtaposed to one another so people really start to collaborate and interact,” he said. “It will be of tremendous benefit to the other labs, as well as us.”

One of two Howard Hughes Medical Institute (HHMI) investigators on campus, Dr. Markowitz leads a team of close to 30 researchers focused on studies of the role of gene mutations in the formation of colon cancer. His goal is to one day identify the genetic roots of colon cancer, which could lead to simple tests to determine who is—and who is not—genetically susceptible to the disease.

Dr. Markowitz was recruited from the National Cancer Institute (NCI) in 1987 along with James K.V. Willson, M.D., to launch a colon cancer research effort at Case. Dr. Willson said he has collaborated for more than 18 years with Dr. Markowitz on an understanding of genetics and molecular biology to determine the cause and treatments for colon cancer.

Although Dr. Markowitz said he always had an interest in science, more personal experiences led him down the path to fighting colon cancer.

He majored in physics and chemistry as an undergraduate at Harvard University, and then moved on to Yale University, where he earned an M.D. and a Ph.D. in cell biology. As a first-year medical student at Yale, Dr. Markowitz met a patient with an inherited form of colon cancer. He called the experience “transforming” and said he hoped similar experiences would occur among students working within the Wolstein Research Building.

While a resident in internal medicine at what is now known as the University of Chicago Hospitals & Health System, he decided to specialize in medical oncology. He zeroed in on colon cancer as a research focus at about the same time the disease was diagnosed in his father.

Today, Dr. Markowitz’s work is supported by multi-million dollar grants from the National Institutes of Health (NIH), the HHMI, the National Colorectal Cancer Research Alliance (founded by Katie Couric, Lilly Tartikoff and the entertainment industry) and other sources.

Colon cancer affects one in 15 people, or about seven percent of the population, according to the NIH. It can be a life-threatening condition that affects the large intestine, but if caught early it is a highly curable form of cancer.

Colorectal cancer is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates 106,370 new cases of colon cancer will be diagnosed in 2004.

Discoveries

Dr. Markowitz’s lab is focused on five major research areas: the search for a new family of genes that cause colon cancer to appear in families; the search for colon cancer metastasis genes; the development of blood tests for early detection of colon cancer; the discovery of genes in which alterations drive the progression of colon cancers to their more lethal forms—genes that are damaged, mutated, turned on or turned off; and unraveling the workings of the TGFbeta pathways, which Dr. Markowitz discovered is normally a major anti-colon cancer pathway.

One of Dr. Markowitz’s major findings was the identification of the hMLH1 gene’s role in the development of colon cancer. When the gene is defective and shuts off, the cancer develops in people who have no family history of the disease. Turning the gene back on in people with colon tumors may make the cancer more responsive to chemotherapy.

Collaborating with Dr. Willson, Dr. Markowitz’s team also found that colon cancers develop a mutated gene for the RII protein receptor, and that this mutation disrupts the normal process of the colon shedding its inner lining once a week. RII is the sensor for TGF-beta, a hormone that normally limits the ability of cells to grow into cancers. When a genetic mutation prevents RII from functioning, the unrestrained cell growth sets the stage for the development of cancer.

Dr. Markowitz and his team also discovered a colon cancer suppressor gene—helicase-like transcription factor (HLTF)—the inactivation of which appears to contribute to malignancy in about 40 percent of cases. They found that reactivating the genetic protein appears to be related to suppressing colon cancers. The methylated HLTF gene could be a target for a new diagnostic test for colon cancer because Dr. Markowitz’s laboratory previously had found abnormal methylated DNA in the blood of some colon cancer patients.

In a nutshell, Dr. Markowitz and his team are working to find new ways to detect people at risk for the disease, to find new ways to diagnose the disease earlier, and to identify new targets for drug development.

The opening of the Wolstein Research Building, he said, is an opportunity for Case to create a renowned center for cancer research. “Case has a wonderful opportunity here to make more visible the cancer research center, to bring cancer researchers together to create a really interactive group of investigators that can do more together than they can apart,” Dr. Markowitz said.

Dr. Willson added that the opening of the Wolstein Research Building would make the sum greater than the parts by bringing together a critical mass of investigators to share their expertise and interests.

The Case Comprehensive Cancer Center, a joint venture between Case, University Hospitals of Cleveland, and now also the Cleveland Clinic Foundation, is one of 38 comprehensive cancer centers across the country recognized by the NCI as Centers of Excellence. Dr. Markowitz says that having this new lab space will allow the cancer center to recruit new researchers, postdoctoral students and others to join the cause and build a worldwide reputation for cancer research.

“The opportunities created by having the new space are enormous,” he said.