A cancer leaves few to lobby

Pancreatic form so deadly, CMU prof is unusual in seeking a cure

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When Randy Pausch testified to Congress a month ago about the need for more pancreatic cancer research money, the most unusual part of his appearance was the fact that he was there at all.

Pancreatic cancer is the deadliest major malignancy on the face of the planet, killing 95 percent of its victims within five years.

That means there are rarely survivors available to lobby on behalf of curing the disease, let alone a patient like Dr. Pausch, a Carnegie Mellon University computer professor who last week released a book on his life story and was the focus of a major ABC TV special.

"One problem with raising awareness of this disease is that unlike with breast cancer or AIDS, our survivors usually don't live long enough to become true advocates," says Julie Fleshman, president of the Pancreatic Cancer Action Network.

Because of that, and the fact that it is a relatively rare cancer, with a little more than 37,000 new cases a year in the United States, pancreatic cancer gets by far the least research funding from the National Cancer Institute among the five most lethal malignancies.

It's not for lack of interest, said Dr. James Doroshow, the institute's director of the division of cancer treatment and diagnosis. "If I don't get asked again this year by the director's office, 'What are you doing to enhance the number of pancreatic cancer research grants?,' I would be amazed -- and I don't hear that question about any other type of cancer."

The problem, from his perspective, is that too few researchers are seeking money for the disease.

But pancreatic cancer researchers say that if there were more money available, more scientists would focus on the disease. In an attempt to attract more interest from researchers, the Pancreatic Cancer Action Network is asking Congress to earmark $170 million in dedicated research funding over the next three years.

Until pancreatic cancer can generate more money for laboratory work and clinical trials, progress will remain slow, said Dr. David Whitcomb, a cancer research director at UPMC's Hillman Cancer Center.

In 1973, before the advent of CAT scans and other modern diagnostic tools, the average life expectancy for someone diagnosed with pancreatic cancer was three months, he said. Today, despite scanners and other specialized tests, the average is four months.

One reason for the lack of improvement, Dr. Whitcomb said, is that pancreatic cancer is insidiously virulent.

There are two reasons for that.

First, it tends to be discovered late, partly because its symptoms of bloating and abdominal discomfort mimic other conditions, and partly because there is no effective screening test for it.

"We don't have a Pap smear, we don't have a colonoscopy, we don't have a PSA test for pancreatic cancer," said Dr. Anirban Maitra, a pancreatic cancer researcher at Johns Hopkins University in Baltimore. "We badly, badly need a screening marker for this disease."

The second problem is that pancreas tumors hijack the body's own defenses to prolong and spread the cancer.

"Pancreatic cancer is probably one of the most deadly cancers because it's resistant to chemotherapy and radiation therapy, it spreads very quickly and the amount of actual cancer necessary to kill a person is very low," said UPMC's Dr. Whitcomb.

Pancreatic cancer recruits immune cells that normally heal wounds and uses them to form scar-like, fibrous sheaths around the tumors.

The sheaths not only help shield the tumors from chemotherapy and radiation, Dr. Whitcomb said, but protect them from a substance produced by the body known as tumor necrosis factor.

As a result, he said, the necrosis factor attacks the patient's healthy tissues instead of the tumors, causing people to waste away and die much more quickly than they would otherwise.

Obviously, then, pancreatic cancer is devious and deadly, but there are some hopeful avenues opening up in research labs around the nation.

One is in cancer vaccines, where research at Johns Hopkins and UPMC has shown some early promise.

In Baltimore, Dr. Elizabeth Jaffee has been working for years on a vaccine that uses modified pancreas tumor cells to trigger an immune response.

In her latest group of 60 patients, she has been able to stretch life expectancy by about five months on average. But three of her original eight patients have now lived cancer-free for 10 years, "and frankly, we were shocked to see that good a result."

Dr. Jaffee has found that the patients who respond best to the vaccine have more of a tumor protein called mesothelin, and her team is now working on developing a vaccine that would use the mesothelin itself as the triggering factor.

In Pittsburgh, Dr. Olivera Finn is trying out a vaccine that uses a different tumor molecule. In her latest group of 12 patients, who had their pancreas tumors removed surgically and then got the vaccine as a follow-up, nearly half are still alive five years later, she said.

Johns Hopkins' Dr. Maitra is taking another approach to stopping the spread of the cancer.

In any solid tumor, he said, there is a small subset of cells, known as cancer stem cells, that are the most dangerous ones, and they are the ones most resistant to standard treatment.

"Our approach to cancer therapy has been all wrong, which is why so many patients come back with relapses," he said. "It has been based on watching cancer shrink, and if we get shrinkage we are happy. The problem is, the cells that are shrinking are not the cancer stem cells. They actually survive most conventional therapies."

So the trick is to find a way to shut down the stem cells, Dr. Maitra said, and he believes he has found a good target in a gene with the odd name of hedgehog.

The hedgehog gene promotes cell growth, a key reason cancer spreads. It got its name because scientists working with fruit flies found that when they eliminated the gene, the flies got hedgehog-like spines all over their bodies.

With the help of drug companies, Dr. Maitra's lab has found substances known as small molecule inhibitors that seem to dampen the hedgehog gene, and they are hoping to try out that treatment in human patients in one or two years.

If this therapy works, Dr. Maitra said, it holds out the hope of turning pancreatic cancer into a disease that people could live with indefinitely.

"I don't think we can completely prevent cancers," he said. "The point is, can we get it down to a level where it's sort of like asthma or Crohn's disease or something you can basically live with, where it's not a disease where you're confined to a deathbed right away."

On the early detection front, a young researcher at Massachusetts General Hospital in Boston named Kimberly Kelly said she has identified a molecule on the surface of pancreatic cancer cells called Plectin 1 that could be used for screening.

The best early warning, though, would be finding a genetic profile for pancreatic cancer, so that people at risk of getting the disease could be identified before any tumor cells start growing.

At Johns Hopkins, one group will soon release the results of analyzing the entire genome of several pancreatic cancer patients to determine mutations that are characteristic of the disease.

That's an important step forward, Dr. Whitcomb said, but even then, scientists will face years of work to determine what effect the various genetic mutations are creating in the body.

One important development that could emerge from such genetic profiling would be to find out which patients with adult diabetes also have the potential to get pancreatic cancer, said Dr. Gloria Petersen, a geneticist at the Mayo Clinic in Rochester, Minn.

About 80 percent of pancreatic cancer patients have elevated blood sugar that shows up two or three years before they get tumors, she said. The trouble is, only 1 of every 125 adult diabetes patients will go on to get pancreatic cancer, and no one has figured out a way yet to pick them out of the crowd.

Genetic testing may one day allow doctors to tell which new diabetes patients are susceptible to getting the cancer.

When Dr. Pausch testified before Congress, he said he believed the solution to treating pancreatic cancer would come from young researchers with new ideas.

Ms. Fleshman, of the Pancreatic Cancer Action Network, agrees, and said that is why her organization and another pancreatic cancer group, the Lustgarten Foundation, are channeling many of their research grants to junior scientists.

But she also said having Randy Pausch as a high-profile spokesman for the disease has been invaluable.

There has been a spate of celebrities afflicted with pancreatic cancer recently -- opera singer Luciano Pavarotti, actor Patrick Swayze and "Killing Fields" photographer Dith Pran -- but only Dr. Pausch has lived long enough and been open enough to speak out about the disease.

"What he has done in the last six months is absolutely amazing," Ms. Fleshman said. "When he came to testify before Congress, I thought, what we've been waiting for is someone to come forward and say we have to do something about this disease, and we've never had that before.

"If we'd have had someone like that 10 years ago," she said, "where would we be by now?"

Mark Roth can be reached at mroth@post-gazette.com or at 412-263-1130.


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