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The Cure: Western Pa. has become an important player in the fight to stop cancer

| Monday, May 7, 2007

It should have been the end.

Doctors in New York believed they did everything they could to help Dr. Harvey Herberman fight cancer. They told him last year to go home and die comfortably.

The Manhattan urologist wasn't ready to give up -- nor was his only brother, one of the nation's top cancer researchers who has directed the University of Pittsburgh Cancer Institute since its founding in 1984.

“He was absolutely determined to fight to the absolute end,” Dr. Ronald Herberman said of his brother.

In offices cluttered with research papers, in laboratories humming with high-tech machines, in hospital hall labyrinths, hundreds of men and women in Western Pennsylvania are fighting to save the half-million Americans who will die from cancer each year. Some are driven by personal reasons, including the loss of a loved one. Others are over-achievers who see cancer as the ultimate challenge.

They probably won't find “The Cure,” because a single cure likely does not exist. Cancer isn't one disease; it describes more than 100 disorders with causes ranging from genetic mutations to viruses.

They probably won't find fame. By collaborating with scientists in America and around the world, researchers gain access to data, ideas and patients, but lose the opportunity to be the only name associated with a discovery.

Yet local researchers keep trying. In the past three decades, Western Pennsylvania has positioned itself as a center for cancer research with promising possibilities to be a major player in the next cancer breakthrough. Pitt ranks 11th nationally in research money from the National Cancer Institute -- up from 74th in 1975.

A few Pittsburgh researchers hold prestigious titles in the $104 million Hillman Cancer Center in Shadyside and can claim breakthrough discoveries. Many more report to humble, closet-sized offices in century-old university buildings and work 80-hour weeks, juggling a passion for research, a desire to teach and the bureaucracies of grant-writing.

They are seeking cures in almost every field of science -- chemistry, biology, sociology, pharmacology.

“We never say no, we never say die, we never give up,” said Dr. John Kirkwood, chief of the division of medical oncology at Pitt's School of Medicine.

The ties that bind

Kazunori Koide, an assistant professor in Pitt's department of chemistry, has a windowless office about the size of a walk-in closet. He has spent six years creating a powerful anti-cancer molecule he named meayamycin. Koide and his team -- graduate students, postdoctoral researchers and collaborators -- have spent an estimated 33,000 hours on the molecule, a microscopic byproduct of bacteria the team altered in the laboratory so it would have a long enough shelf-life to be used in patients.

Meayamycin stops breast and cervical cancer cells from multiplying in petri dishes. A Japanese pharmaceutical company that discovered the “orphan” molecule abandoned it because the company didn't want to focus on cancer drugs.

Although the molecule shows potential, there is no guarantee it will become medicine. Millions of dollars and several years of research are necessary. Koide doesn't know why the molecule disables the cancer. He must create a drug -- which then must be tested in animals and show promise in human clinical trials before it could win approval from the U.S. Food and Drug Administration.

The odds of that happening are less than one in 5,000, according to the Pharmaceutical Research and Manufacturers of America, which advocates for drug companies.

Koide is undeterred.

“I've always been interested in the cure for cancer,” he said. “I lost my father to cancer about 30 years ago when I was 9, and I was wondering why the doctors couldn't do anything.”

Aleem Gangjee, a professor of medicinal chemistry at Duquesne University's Mylan School of Pharmacy, is similarly driven. Breast cancer killed his grandmother and three aunts.

He holds four federal grants, totalling $5.3 million, to develop anti-cancer drugs. The money buys equipment and chemicals and pays graduate students' salaries.

When Gangjee became a cancer researcher more than 25 years ago, he didn't think he'd still be chipping away at a cure today.

“In the 1970s, when I started, I told everyone we would cure cancer in 10 years.”

Team science

Researchers agree there will be several hundred cures -- tailored to types of cancers and to the genetic make-up of tumors. Genetic differences in breast cancer tumors, for example, determine different treatments.

“There's not going to be one cure,” said Dr. Laura Niedernhofer, assistant professor of molecular genetics and biochemistry at Pitt's School of Medicine. “The magic bullet theory went out the window a long time ago.”

Early detection, reduced environmental risk, better drugs and genetic therapy are credited with pushing cancer survival rates from 50 percent in the 1970s to 65 percent today.

The scientific immortality bestowed on Jonas Salk for creating a polio vaccine and to Sir Alexander Fleming for discovering penicillin likely won't be accorded a cancer researcher.

“It's probably going to be very difficult to point to one person and say that's the person who made the cancer cure breakthrough,” Herberman said. “More and more, these advances are coming through team science.”

At least 128 scientists and doctors in 19 countries deserve credit for the discovery, development and testing of Tykerb, said Dr. Charles Geyer, director of Breast Medical Oncology at Allegheny General Hospital in the North Side. Geyer led clinical trials for the drug and announced in January that it effectively fights a type of breast cancer that sometimes doesn't respond to other drugs.

“It is a massive enterprise, developing a cancer drug, and people who aren't around it tend to think in terms of that there's one researcher in the lab who makes the discovery,” Geyer said. “It's not that way. It's a process that evolves over many, many years.”

Pitt's Cancer Institute uses team science to find a cure for melanoma, the deadliest form of skin cancer, which kills 7,000 people in the United States each year. Thirty scientists, under Kirkwood's direction, share ideas and questions and collaborate on research papers.

Melanoma patients in clinical trials through the program meet with doctors who administer the treatment and researchers who invented it. Scientists and patients say this interaction humanizes the research.

“They discussed it thoroughly with me,” said Gerri Dacko, 61, of Beaver Falls, who was told in 2004 that cancer likely would kill her within a year. “They were wonderful and patient, and answered all my questions.”

She participated in a clinical trial that stimulates a patient's immune system to fight cancer. Her cancer is not gone, but is being managed.

A vibrant, active woman who laughs easily, she enjoys gardening and hosting tea parties. “

I truly believe that I am a miracle,” she said.

The Cures

Researchers are attacking cancer from many fronts.

Herberman and Kirkwood are exploring the human immune system for ways to make the body cure itself. In the 1970s, Herberman helped discover “natural killer” cells that can be stimulated to inhibit cancer growth. For a few decades, Kirkwood has worked with interferon alpha-2b, a drug that mimics an immune system infection-fighting protein and, in 2001, declared it effective therapy for high-risk melanoma patients when coupled with surgery.

Duquesne pharmacology professors Paula Witt-Enderby and Vicki Davis are learning how the hormone melatonin, produced when people are in darkness, might protect women against breast cancer while they take hormone replacement therapy.

Dr. Emanuela Taioli, director of the cancer prevention and population science division at Pitt's Cancer Institute, is studying environmental and health-related causes of cancer and ways to avoid them. The goal is to prevent cancer from occurring.

The National Surgical Adjuvant Breast and Bowel Project, directed by Dr. Norman Wolmark at Allegheny General, has enrolled more than 110,000 patients in clinical trials at 250 institutions worldwide over 35 years, to test what works and what doesn't.

Theresa Whiteside and Albert DeLeo, professors of pathology and immunology at Pitt's School of Medicine, recently began a clinical trial to test a vaccine for head and neck cancers. It strengthens the body's natural defenses against cancer and prevents recurrence.

Tom Conrads, co-director of the Pitt Cancer Institute's Clinical Proteomics Facility, is developing blood tests to reliably detect cancers, such as prostate and ovarian, in early stages.

Searching for cures requires working long hours and continuing despite disappointing results.

“What keeps me going ... is the fact that I walk through the same revolving door that up to 800 cancer patients walk through every day,” said Conrads. “And that's very sobering.”

Defeating a villain

Though most cancer researchers eventually know people affected by the disease, not all enter the field because of a personal vendetta against cancer.

“It's the most exciting career I can think of,” Niedernhofer said. “It's like (cancer) outsmarted us, it's this great villain.”

In junior high school, Lisa Butterfield, associate director of Pitt's Immune Monitoring Laboratory, wrote a report on a rare genetic disease called Lesch-Nyhan Syndrome. Learning how it worked made her believe there could be a cure, though one doesn't exist. She applies that attitude to her research.

“In cancer we have an incredibly fascinating -- from a scientific view -- disease,” Butterfield said. “The promise is there. We can figure out everything that's wrong. We've cured people with stage four cancer. It works. Once you do that, there's no going back.”

Some researchers struggle to describe their passion for finding a cure.

“I wish I could tell you ever since I can remember I wanted to cure cancer, but that's not how it was,” said Wolmark, who was an aspiring biochemist before going to medical school.

As he learned about cancer, he realized he had the scientific skills to do more than treat the disease.

“Will we cure everybody• I think we'll see that day,” he said.

Ronald Herberman's professors in medical school encouraged him to pursue cancer research, a career he began 40 years ago.

When his older brother was diagnosed 20 years ago with indolent lymphoma, a slow-killing blood cancer, he had reason anew to seek a cure. Harvey Herberman accompanied his brother to research conferences and the two discussed discoveries.

Ronald Herberman continues looking for a cure, without his brother by his side. Harvey Herberman died at UPMC Shadyside on March 4, a week before his 69th birthday.

“I found the whole situation -- particularly as a cancer professional, a cancer researcher -- particularly frustrating and poignant,” Herberman said. “But I truly believe that by bringing him here ... we were able to keep him alive at least a year longer.

“That gives me a lot of comfort.”

Breakthroughs for the region

Western Pennsylvania researchers have made numerous breakthroughs in cancer prevention and treatment, including:

  • Breast conserving operations : In 1971, the National Surgical Adjuvant Breast and Bowel Project -- begun at the University of Pittsburgh and now at Allegheny General Hospital -- enrolled 1,600 women in a clinical trial for breast cancer surgery. It would find that less invasive procedures could replace disfiguring or disabling operations. By 1975, the project showed that total mastectomy, or breast removal, was as effective as radical mastectomy, where the breast, chest wall muscle and underarm lymph nodes are removed. In 1976, more than 2,100 women entered another study that showed lumpectomy, or removal of the tumor and some surrounding tissue, coupled with radiation therapy could work as well as a mastectomy.

  • Interferon : In 2001, Dr. John Kirkwood, director of the University of Pittsburgh Cancer Institute's Melanoma Center, announced that extensive clinical trials he led in the late 1990s found an effective treatment for melanoma, the deadliest form of skin cancer which kills 7,000 people in the United States each year. When used with surgical removal of the cancer, Interferon alpha-2b reduced by 33 percent the likelihood that patients would relapse and die. Interferon alpha-2b is a man-made version of immune system proteins that fight viruses and bacteria.

  • Herceptin : In 2005, NSABP-led, large-scale clinical trials on the breast cancer drug Herceptin were stopped early because the drug was so effective that further studies weren't needed. Patients who received Herceptin with chemotherapy had a 52 percent decrease in cancer recurrence compared to patients treated with chemotherapy alone. Herceptin works on the 20 percent of breast cancers where the tumor is overloaded with a protein called HER-2.

  • ABT-627 : In the mid-1990s, researchers led by Dr. Joel Nelson, co-director of the Pitt Cancer Institute's comprehensive prostate and urologic cancer center, found a protein called endothelin-1 in patients with advanced prostate cancer. The protein appeared to contribute to the growth and spread of cancer to the bones, causing pain, so Nelson began searching for something to stop it. In 2001, Nelson reported a drug called ABT-627 blocked the protein from working and decreased pain in men with advanced prostate cancer, who weren't responding to mainstay treatments.

  • STAR : The Study of Tamoxifen and Raloxifene, or STAR, was one of the largest breast cancer prevention studies, taking place at more than 500 centers across the United States, Canada and Puerto Rico. It was conducted by the National Surgical Adjuvant Breast and Bowel Project, which announced in 2006 that the drug raloxifene was as effective as tamoxifen at preventing breast cancer and had a lower risk of blood clots. In 1982, the NSABP found tamoxifen increased survival in breast cancer patients, and in 1998, it showed tamoxifen reduced breast cancer occurrence by 49 percent.

Cancer by the numbers

10,496,000 -- Americans who have cancer

1,399,790 -- Americans diagnosed with cancer last year

73,630 -- Pennsylvanians diagnosed with cancer last year

564,830 -- Americans who died of cancer last year

29,710 -- Pennsylvanians who died of cancer last year

67 -- Average age at cancer diagnosis

41 -- Percentage of people today who will be diagnosed with cancer at some point in their lives

1/3 -- The portion of cancer deaths in 2006 related to nutrition, physical inactivity or obesity

65 -- Percentage of people diagnosed with cancer between 1995 and 2001 who survived five years after diagnosis

50 -- Percentage of people diagnosed with cancer between 1974 and 1976 who survived five years after diagnosis

$209.9 billion -- Overall cost of cancer in 2005, in terms of medical care and lost productivity

Source: American Cancer Society, National Cancer Institute, National Institutes of Health

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