National Cancer Institute Awards $2.4 Million to Fox Chase Cancer Center to Test Cancer Prevention Agents with Jefferson Medical College

PHILADELPHIA (March 21, 2000) -- The National Cancer Institute has awarded a $2.4 million contract to Fox Chase Cancer Center to evaluate potential cancer prevention agents, working with researchers from Jefferson Medical College of Thomas Jefferson University. The two institutions will share the funds over the two and one-half years of the project.

The project will use new DNA microarray technology to study the agents' effects on cells containing altered human genes associated with hereditary risk of a particular cancer. The researchers will compare tissue samples from individuals with the hereditary condition and those without it. Using cell cultures of the various tissues, the scientists will evaluate the activity of the target genes before and after treatment with the preventive agents to be tested.

Lasker Award-winning researcher Dr. Alfred G. Knudson Jr. of Center City Philadelphia, a Fox Chase Cancer Center Distinguished Scientist, is the principal investigator for the contract. Knudson has been internationally honored for his 'two-hit' model of cancer causation, which explains how mutations in a pair of genes can lead to hereditary and nonhereditary cancers.

Knudson's Fox Chase co-director for the contract is Dr. Margie L. Clapper of Harleysville, Pa., a cell biologist who has conducted some of the first studies of chemoprevention-the use of medication to prevent or reduce the risk of disease. Her laboratory focuses on biological markers of cancer risk and their response to chemopreventive drugs with the goal of developing effective medical regimens that can be tested in clinical trials.

Dr. Bruce Boman, director of the division of medical oncology and medical genetics at Jefferson Medical College, is co-director for the portion of the project to be done by Jefferson under a subcontract with Fox Chase. According to Knudson, Boman has nearly 20 years of experience in the molecular genetics of hereditary and nonhereditary colon cancer. His gene discovery program recently led to the identification of 14 previously unknown human genes affecting the lining of the colon.

Overall, the project will test the effects of five chemopreventive agents, using tissue samples from people with one of six inheritable conditions leading to breast, ovarian, colon or kidney cancer. The goal is to identify molecular targets for drugs that can halt or reverse precancerous changes in cells.

"Most adult cancers result from multiple genetic changes that occur sporadically as people grow older," Knudson explained. "But we know of 30 abnormal genes that people can inherit in a dominant fashion-that is, if one parent has the gene, the children will inherit it in every cell of their body. Not everyone who has one of these variant genes will develop cancer, but the risk is greatly increased because fewer sporadic genetic changes are required."

"Studying tissue samples from these people will allow us to look at the earliest, least complicated model of genetic changes that initiate cancer. This gives us the best opportunity for discovering how to reverse these changes through chemoprevention. We have selected six inherited conditions that we consider most representative, which are already being studied by one or more investigators in our group."

DNA microarray technology will permit the researchers to analyze thousands of genes in a sample at the same time. A powerful new tool, microarrays use glass 'chips' to hold thousands of gene segments that can be visualized by a computer. Genes in a blood or tissue sample will bind to the corresponding genes on the chip.

The microarray comparisons of the various tissue samples will be the responsibility of Dr. Steven McKenzie, associate professor pediatrics at Jefferson Medical College. He will use the DNA microarray facility at Wilmington's A. I duPont Hospital for Children, where he is based.

"We're trying to do a broad analysis of as many genes as we can," said Boman, a member of Jefferson's Kimmel Cancer Center. "We're interested in the cancer initiation step-the moment the cell becomes cancerous-because we think it could be reversible with chemopreventive agents."

"The next step is to figure out what those genes tell us, what molecular pathways they are involved in, what families they belong to and what proteins they are responsible for producing. It's tough to know how each gene fits into the large picture of cancer initiation. There are more than 100,000 genes in each cell type and maybe 10 to 20 thousand are expressed."

The microarray technology will let the researchers determine how those genes are expressed-whether they are active, overactive or quiet-in both the normal samples and those from people with inherited cancer risk. After the cell cultures are treated with chemoprevention agents, new comparisons will be made.

Chemoprevention targets include breast and ovarian cancers associated with inherited breast-cancer genes, BRCA1 and BRCA2. This hereditary risk accounts for between 5 to 10 percent of all cases of breast cancer. Fox Chase geneticist Dr. Andrew K. Godwin of Jenkintown, Pa., will conduct this effort.

Annually, breast cancer strikes an estimated 175,000 American women. More than 25,000 a year develop ovarian cancer.

Two inherited forms of colon cancer are an important focus of the contract at both Fox Chase and Jefferson. This effort involves Boman, Clapper and Fox Chase geneticist Dr. Alfonso Bellacosa, who lives in the Fox Chase section of Philadelphia.

Cancer of the colon and rectum affects more than 129,000 Americans a year. It is the fourth most common cancer and the second leading cause of cancer deaths in the United States. More than 25 percent of colorectal cancers may result from genetic factors passed from one generation to the next.

One inherited risk factor is a condition known as familial adenomatous polyposis, which causes hundreds of noncancerous tumors called polyps to grow in the lining of the colon. Eventually, people with polyposis develop colon cancer. The condition is linked with the genes FAP and APC. The researchers will also study hereditary nonpolyposis colon cancer, associated with the HNPCC and MSH2 genes.

Kidney cancer, which affects about 30,000 Americans a year, is another target of the work at Fox Chase. Dr. Joseph R. Testa of Churchville, Pa., who directs the Fox Chase human genetics program, and medical oncologist Dr. Elisabeth Petri Henske of Rydal, Pa., will carry out this research.

The types of kidney cancer involved include hereditary papillary renal carcinoma, linked with the HPRC and MET genes. Another type is renal-cell cancer, the most common kidney cancer, which usually is not hereditary. However, people with a rare inherited disease called tuberous sclerosis have an increased risk of renal-cell cancer because of an inherited defect in the TSC2 gene.

In general, tuberous sclerosis causes bumps on the skin resulting from small tumors of the blood vessels. The disease may also produce seizures, mental retardation and noncancerous tumors in a number of internal organs, including kidney cysts. Among patients who develop a malignant tumor of the kidney, the cancer occurs at unusually early ages, even in children as young as seven.

Fox Chase Cancer Center, one of the nation's first comprehensive cancer centers designated by the National Cancer Institute in 1974, conducts basic and clinical research; programs of prevention, detection and treatment of cancer; and community outreach. In February, the Center opens its new Prevention Pavilion, which houses its comprehensive Research Institute for Cancer Prevention. For more information about Fox Chase activities, visit the Center's web site at www.fccc.edu.

Founded in 1824, Jefferson Medical College is recognized as one of the nation's top academic medical centers. Jefferson's faculty is recognized for its leadership in health research, especially in the area of cancer. For more information, visit Thomas Jefferson University's web site at www.tju.edu.