Vera Svobodova had help in January 1987 when she was clambering over a razor-wire-topped wall to escape communism in her native Czechoslovakia, and help of a different sort years later when she got seed money to jumpstart her cancer research in Pittsburgh.

	Darrell Sapp, Post-Gazette Vera Donnenberg, an investigator with the Hillman Cancer Center, gathers slide samples from lung cancer. The Hillmans will announce today that they are giving $20 million to establish a Hillman Fellows Program at the University of Pittsburgh Cancer Insititute that will provide seed money to young investigators. Click photo for larger image.

That help led to such promising results that today Henry and Elsie Hillman will announce a $20 million donation -- the single largest gift ever for the University of Pittsburgh or UPMC -- to provide seed money for people like Vera Svobodova Donnenberg, now a 38-year-old researcher at the University of Pittsburgh Cancer Institute who still has scars on her hands from those wires, a reminder of her good luck and her invaluable helpers.

Eighteen months ago, businessman and philanthropist Henry Hillman provided $300,000 for Donnenberg's study of what she calls "the Darth Vader of stem cells," the tumor stem cell.

Her findings could lead to a radical change in how cancer is treated and Hillman's initial investment in her work has helped her secure at least $5 million in private and federal research support over the next five years.

Seed funding provided to Donnenberg and 13 other investigators proved so successful that the Hillmans decided to make the $20 million gift to UPCI and the UPMC Cancer Centers to establish The Hillman Fellows Program for Innovative Cancer Research.

The donation from the Hillman Foundation and the Henry L. Hillman Foundation will launch a new initiative to raise $200 million to hire 50 to 100 more researchers and, with 3-year-old Hillman Cancer Center in Shadyside already filled to capacity, build an additional research building.

The Hillman Fellows program will provide a flexible source of funding that can be used to help launch new research initiatives, such as Donnenberg's tumor stem cell work, said Dr. Ronald Herberman, director of the cancer institute.

"Mr. Hillman had been hearing the talk repeatedly that seed money for getting projects started . . . can be difficult to obtain," Herberman said. And a researcher with a novel idea can't go to the National Institutes of Health or any other major funding agency and hope to get a research grant without having already done some work to prove the idea is feasible.

"He told us about a year and a half ago that he had gotten the point," Herberman recalled. On a trial basis, he agreed to provide seed money to a select group of researchers. About 30 researchers submitted proposals; 14 were selected.

'Seed' funding

"The Hillman funding was absolutely crucial," Donnenberg said, enabling her to generate enough findings to garner two research grants from the Department of Defense and support from A Glimmer of Hope Foundation. Reviewers gave high scores to her application for an NIH grant, though no word on approval is expected for weeks.

Her work on the tumor stem cell "has the potential to be revolutionary," Herberman said. The idea is that cancers are the result of damaged stem cells, which then generate tumor cells. If this hypothesis is correct, it means that many cancer therapies are ineffective because they target only tumor cells and not the hard-to-kill tumor stem cell.

"I'm so excited about what we are doing," Donnenberg said, despite a hectic schedule. Most days, she's in her lab by 7 a.m. and her head seldom hits her pillow until well past midnight.

Donnenberg's flight from communist Czechoslovakia 18 years ago dispels any question about her toughness and determination.

The daughter of a political dissident who died during forced labor in Czech uranium mines, Donnenberg was a fine arts major and an aspiring painter when her mother persuaded her to escape. She got her chance when she was allowed to go on a skiing trip to Yugoslavia.

She had hoped her trip would take her to the Alps in northern Yugoslavia, close to the Italian border; instead, she ended up to the south, near Albania.

Undaunted, she began a 300-mile walk to freedom in the dead of winter. For two weeks, she didn't eat. But the bigger problem was sleep.

"Walking in winter, you can't sleep," she explained. "If you sit down somewhere, you freeze."

By the time she reached Belgrade, she was frostbitten and malnourished. She was befriended by people who nursed her and then helped her, via train and hitchhiking, to reach the Italian border.

In the border town now known as Nova Gorica, Slovenia, sympathetic Yugoslavians distracted the guards long enough to give her time to scale the wall. A hail of bullets eventually came her way, but she got over the wire-topped wall and dropped safely to freedom in Gorizia, Italy.

Once safely in Italy, she stayed with family friends. A year later, she came to the United States and Baltimore. Though she had aspired to be an artist in Czechoslovakia, where artists are supported by the state, it didn't take her long to figure out that being an artist in America is much harder.

Unable to speak English, she worked at McDonald's and other odd jobs until she landed a technician's position in clinical pharmacology at Johns Hopkins University. Within five years, she had received a master's degree in pharmacology, obtained U.S. citizenship and won a Distinguished Citizen award from the Maryland governor.

Also, she met her future husband, Albert Donnenberg, when she went to his Johns Hopkins lab to learn how to separate white blood cells.

She moved to Pittsburgh in the early 1990s after Albert Donnenberg joined the Pitt medical school, where he is deputy director of the stem cell transplantation program. She subsequently began doctoral studies in the Pitt School of Pharmacy.

Donnenberg did research related to organ transplants, studying how cells in transplant patients develop resistance to multiple drugs. That poses a problem when the cells are resistant to the immunosuppression drugs used to prevent rejection of transplant organs.

Her cancer work began in 2002, after she earned her doctorate and joined the faculty. She was unsure what direction to take, but decided to study the tumor stem cell hypothesis at the suggestion of UPMC President Jeffrey Romoff.

Romoff is known for his financial and administrative prowess, not for science, but in this study, Donnenberg said, "I probably should make him my co-author." Since his bout with prostate cancer in the late '90s, she explained, he has had a particular interest in cancer and he was intrigued by the notion of the tumor stem cell.

"The idea that cancer comes from tumor stem cells is older than I am," said Donnenberg, an assistant professor of surgery and pharmaceutical sciences.

Stem cells have received a lot of popular and scientific attention lately because they can give rise to new tissues and thus might be used for regenerative medicine. But they have some features that are similar to cancer cells. Stem cells are seemingly ageless and can divide endlessly, producing an array of specialized "daughter" cells.

And they are resistant to any number of toxins. "Stem cells are very, very protected cells," she said. In that regard, her expertise in studying multiple drug resistance in cells put her in good stead.

Off target

The conventional view of cancer is that it occurs when a cell's genetic material is damaged in such a way that it begins dividing uncontrollably. A tumor thus would consist of malignant cells, all dividing endlessly.

But the tumor stem cell hypothesis argues that cancers only occur when a stem cell becomes damaged and begins producing large numbers of tumor cells. It is the tumor stem cells that are most dangerous; without them, the tumor would not grow.

"If this is entirely correct, then most of the efforts we're expending to treat cancer may be a little off target," Herberman said. Chemotherapy and radiation can readily kill most of the cells in a tumor, but they may not kill the tumor stem cells. So a cancer can appear to be in remission, but if the tumor stem cells remain, the cancer will recur.

"We know we can kill bulk tumors," Donnenberg said. "But we're just killing the progeny, the daughters of the stem cells."

It doesn't take many tumor stem cells to generate a tumor. Donnenberg said only between one out of 10,000 to one out of a million cells in a tumor are tumor stem cells. "In a regular examination, you could never see them," she said. In her lab, she finds them by grinding up a tumor and using enzymes to eat away the non-stem cells.

Just as the idea of tumor stem cells isn't new, Donnenberg isn't the only researcher studying them. Pioneering work has been done in recent years at the University of Michigan and Stanford University, among others.

Still, "in just a very short time, Dr. Donnenberg has become one of the leading scientists in this area," Herberman said.

Thus far, Donnenberg has isolated tumor stem cells from 30 types of solid tumors, including lung, breast, prostate and ovarian cancers, and 29 types of metastatic tumors ---- cancers that have spread from other organs. She cultures these cell lines in her labs and compares them with 70 cell lines derived from adult stem cells obtained from normal tissues.

By comparing the genetic makeup of the normal and tumor stem cell lines, Donnenberg hopes to identify unique features of the tumor stem cells that might become targets for future cancer therapies.

Proving that tumor stem cells are the culprits in the cancer story is difficult, but she knows that finding their vulnerabilities and exploiting them will be even more difficult.

"I get stomach aches just thinking about it every day."