Tackling cancer's mysteries

by David Rumbach

SOUTH BEND — Researchers at the University of Notre Dame will be getting $2 million more to unravel the inner workings of cancer cells and to pioneer new treatments and diagnostic tools.p. ND’s research program — called the Walther Cancer Research Center — is in line to receive the money from the Department of Defense. A bill appropriating the funds has been approved by both houses of Congress and is awaiting the president’s signature.

The grant will allow the center to expand a variety of projects being carried out by three groups of researchers, said Rudolph Navari, Walther Center director. The ND scientists in those groups are among researchers around the world who are delving into the molecular intricacies of cancer.

Thorny questions

Among the thorny issues they’re pursuing are the questions of how tumors coax nearby blood vessels to grow toward them and supply them with nutrients and oxygen and how individual cancer cells learn to change shape so they can flow through the bloodstream and spread to other organs.

The insights such researchers are finding seem, on the one hand, to make cancer seem all the more formidable, even cleverly malicious. But, in fact, understanding cancer on the deepest level of biochemical processes reveals strategies to diagnose and defeat it, Navari said.

For example, detailed study of angiogenesis — the process by which tumors hijack blood supplies — has led to the discovery of a protein fragment that appears in the urine of colon cancer patients at the same time tumors recur, Navari said.

The existence of that fragment suggests a new test that doctors might one day use to detect the recurrence of colon cancer much more quickly, when treatment works best and lives can still be saved.

“We know our current techniques (for detecting recurrence) are not very good,‘’ said Navari, a medical oncologist. "A CT scan, for example, only finds tumors that are 2 centimeters or more. The hope is that this will allow us to detect it much sooner.’’

Grant favors collaboration

The Department of Defense grant program now funding ND gives preference to research centers that stress collaboration between university departments, Navari said.

The Walther Center’s three teams of researchers are drawn from the chemistry, biochemistry, biology and premedical departments, he said. A fourth group, not involved in the new grant, explores ethical and social questions related to cancer care that people receive.

By working together, scientists from different disciplines hope to cut the time it takes to discover new treatments and advance them to clinical research. It’s not unusual for 20 years to lapse between the discovery of a potentially useful new cancer-fighting chemical and its actual use in people with cancer.

“Traditionally, departments work independently, and even within departments, professors pretty much do their own thing,‘’ Navari said. "One of the things we try to do here is to get people to talk to each other.’’

While chemists are making new molecules with potential for fighting cancer in the lab, biochemists and biologists are learning more about the molecular processes that make cancer tick. They can assess the effect of potential new drugs on healthy and malignant cells.

As a physician who treats patients in South Bend, Navari said he contributes a sense of what drugs and tests are needed most for people with cancer.

“I can identify the areas, particularly in breast and prostate cancer, where we don’t have good treatments,’’ he said.

Cells targeted for genetic analysis

The cancer work is being done at labs in buildings throughout the campus. The researchers come from across the country and around the world and include both undergraduates in their early 20s and established scientists.

In one of the labs, Matt Feldman, a graduate student in biochemistry, uses two high-tech devices to explore subtle genetic differences in healthy and cancerous mice.

Feldman uses a laser capture microdissector to isolate individual cancer cells from mouse tissue. He can even hand-pick cells from the border between cancerous and normal tissue, and then compare healthy and diseased cells that were, literally, next-door neighbors.

After being isolated by the microdissector, sick cells are analyzed using a device that compares their entire genome, consisting of 6,000 genes, to those of three normal mice. The normal mice genomes are contained within small plastic chips, called microarrays, that cost $750 each and can only be used once, said Victoria A. Ploplis, associate chemistry and biochemistry professor.

The purpose of the genetic analysis is to find variations in gene expression that are associated with the disease, Ploplis said. Since the researchers are looking at the entire genome of the mouse, it’s possible for entirely unexpected genes to emerge as key players in disease.

“This is discovery research,‘’ Ploplis said. "We’re looking at everything.’’

The mice used by the gene-targeting group at the Walther Center are produced in the university’s Transgene Center. They are genetically altered to produce too much or too little of various proteins, enabling researchers to explore how various abnormalities influence cancer and other diseases, Director Francis Castellino said.

Looking to mice for answers

Research at the Transgene Center, which keeps an inventory of 5,000 transgenic mice, focuses mainly on genes and proteins involved in blood-clotting, Castellino said. Abnormal clotting is, of course, a factor in heart attacks and atherosclerosis, but it’s associated with cancer as well, Navari said. Physicians have long observed that cancer patients often develop abnormal clotting.

“We have taken these mice, which are deficient in certain clotting proteins, and transplanted tumors into them and found the tumors grow a lot slower,‘’ Navari said. "So maybe it’s possible to design a drug to reduce this protein in cancer patients, and slow down the cancer growth.’’

In a chemistry lab, Pingyu Ding, a visiting scholar from China, synthesizes a promising new molecule believed to have the remarkable ability to attach itself to the surface of prostate cancer cells, and not to anything else.

The excitement about this compound, called a prostate specific membrane antigen, is that it might lead to a screening test that is far superior to the largely ambiguous PSA test now given to middle-aged men, said Paul Helquist, chemistry and biochemistry professor.

One could, for example, attach a fluorescent compound to the molecule so that when it binds to prostate cancer cells, they light up on diagnostic scans and reveal their presence, said Helquist, who heads up the Walther Center’s drug design group. Or one could go one step further and attach a cell-killing drug directly to the molecule, enabling it to seek out prostate cancer like a smart bomb.

Hope from a sea slug

Another promising molecule being studied by the chemistry department is derived from a black sea slug found on a Japanese island just off Okinawa. The extract from the ugly slugs — which look like "balls of tar,’’ Helquist said — was identified as a potential anti-cancer agent 12 years ago. But the information sat unused until recently when a researcher named John Kane isolated the active chemicals and start making it in the lab at Notre Dame.

Lab tests have confirmed that very tiny amounts of the drug cause breast cancer cells to break up and self-destruct, Helquist said. The next steps are to make sure the compound, called iejimalide, doesn’t do the same thing to healthy cells and to see whether it works in living mice.

“That’s the extent of work that could be done at a typical university,‘’ Helquist said. "If a compound meets all these tests, there would be a transfer of technology to a pharmaceutical concern.’’

What makes cancer spread?

In the biology department, Crislyn D’Souza-Schorey is exploring one of cancer’s most dangerous tricks: the ability to detach from its site of origin, change shape and move around the body to invade different organs. Her research looks specifically at breast cancer and other cancers that occur in surface tissues called epithelia.

Her research feeds into one of the great mysteries of cancer: What triggers cancerous tumors to begin spreading, she said.

“The ultimate goal is to control or prevent metastasis,’’ she said.

The cancer research at Notre Dame is not unusual. Universities around the world are doing similar work. It is unusual, however, for Notre Dame to be as heavily involved in medical research as it is, given the fact that it does not have a medical school.

“You won’t find another chemistry department in the country doing what we’re doing,’’ Castellino said.

The new grant approved by Congress is the second one that the Defense Department has awarded to ND, Helquist said. The original grant, now being used, was for $1 million

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