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Here are just a few of the ongoing projects at Duke University Medical Center and Duke Comprehensive Cancer Center.

New therapy to treat lung cancer

Duke physician Dr. Thomas D'Amico is treating lung cancer patients with "cool" laser energy to help a drug kill cancer cells while leaving normal cells alone.

The treatment, called photodynamic therapy, was approved by the FDA for early stage lung cancers in January 1998, but was just approved for use with advanced lung cancers late last year. Duke is one of two medical centers in the southeast that regularly treat lung cancer patients with photodynamic therapy. The treatment removes tumors that are blocking airways such as the trachea or bronchi.

"For some early-stage lung cancer patients who can't be treated with surgery, this therapy could possibly be curative," explains D'Amico, a thoracic surgeon.

Photodynamic therapy combines aspects of chemotherapy, radiation and surgery. First, a drug called Photofrin is given to the patient. The drug accumulates in cancer cells and makes them sensitive to light. About two days later, the physician uses a bronchoscope to guide an optic fiber through the trachea and to the tumor. A special non-heating laser is used to activate the drug, which then stimulates production of deadly oxygen radicals - the same type of highly reactive oxygen produced by standard radiation treatments. The end result is the same as surgery with a heating laser, but is less risky.

"Using a heat-producing laser is not only more time intensive, it's also more dangerous," says D'Amico. "With photodynamic therapy, it's easier to control the depth of tumor treated, reducing the risk of rupture."

Keep the best, forget the rest

One of the hottest topics in cancer treatment is using stem cell transplants to boost the body's immune system after high-dose chemotherapy kills all the cancer cells. The idea is sound - give as much chemotherapy as necessary to destroy every last cancer cell and then help the body recover by giving back its own stem cells to rebuild all the body's blood cells - but it's not perfect. When patients are treated with high-dose chemotherapy and stem cells, the cancer still returns in some cases.

There could be two alternate explanations for this, says Dr. James Vredenburgh.

"There may be cancer cells that are resistant to the chemotherapy drugs," he says. "The other explanation is that all the cancer cells in the body were killed, but some cancer cells were actually given back to the patient in the stem cell transplant."

While science is still addressing chemotherapy resistance, there may be a way to avoid the second possibility. Vredenburgh is using a process created by a company called Nexell. They have developed an antibody to a protein called CD34, which is found only on the outer membrane of stem cells. The researchers collect the patient's blood, then pour it over a surface that contains the CD34 antibody. The stem cells stick to the surface, while the other cells are washed away.

For patients with a very high risk of cancer recurrence, the process decreases the chances that tumor cells are accidentally returned to the patient. The extra-pure stem cells are then collected and given back to the patient. Dr. Vredenburgh is preparing detailed information on the value of this procedure to present at the American Society for Clinical Oncology meeting May 15 in Atlanta.

Duke joins NCI Pediatric Brain Tumor Consortium

The Brain Tumor Center at Duke has become part of a new national network of medical centers evaluating promising treatments for children with brain tumors.

As one of nine academic centers across the country participating in the National Cancer Institute's Pediatric Brain Tumor Consortium, Duke will work to conceive, develop and carry out pilot studies and early trials of promising new therapies.

"We're making new strides in treating and curing brain tumors," said Dr. Henry Friedman, co-director of Duke's brain tumor program. "Being part of this consortium will give us the added advantage of working together with other top researchers in the field."

Researchers are targeting brain tumors with a number of new biological therapies and chemotherapy regimens, as well as new surgical procedures and radiation treatment. Among treatments in development are drugs targeted at specific proteins in malignant cells, new radiosurgery techniques, drugs that modulate the immune system to fight tumors, new ways of delivering drugs directly to a tumor and new approaches to gene therapy, according to the NCI.

The consortium is expected to enroll 80 to 100 patients a year in three to four clinical trials, with the first trials opening for enrollment in September.

Tumors' rhythm may upset treatment plans

Duke researchers have shown oxygen levels and blood flow rates fluctuate rapidly in tumors, perhaps enough to prevent chemotherapy and radiation therapy from working as effectively as possible. Until now, oxygen levels were thought to be relatively stable, regardless of how much oxygen was present.

The large fluctuations in oxygen levels might mimic a condition known as hypoxia-reoxygenation injury, says radiation oncologist Mark Dewhirst. When tissues are starved of oxygen, as in a stroke, the tissue is damaged. But the treatment - restoring oxygen - can cause additional damage through an enzyme called xanthine oxidase, which makes oxygen radicals that cause more cellular damage. Cells that survive hypoxia-reoxygenation injury protect themselves somehow from the additional damage.

Dewhirst, who presented the data at a recent American Association for Cancer Research meeting in Philadelphia, wonders if the fluctuations they've seen in oxygen levels might be large

enough to be similar to hypoxia-reoxygenation in the cells. If so, the cancer cells might be building up defenses against oxygen radicals, making radiation therapy ineffective. Dewhirst says further study is needed, but he is intrigued by the fluctuations and is now looking for their causes and effects.

One possible cause for the changes is a process called "vascular remodeling," in which blood vessels are quickly formed and quickly die, rapidly altering the blood flow patterns in the tumor. This could cause both blood flow rate changes and oxygen level changes.

The researchers will be testing this hypothesis by using angiogenesis inhibitors to prevent blood vessel formation, thus blocking one aspect of vascular remodeling. Other work at Duke (see below) may help them with that goal.

Angiostatin binding site characterized, paving the way for simpler analogs

Now that Duke University Medical Center researchers appear to have answered one of cancer's enigmas, they are working on applying that understanding to clinical treatment.

In the March 16 issue of the journal Proceedings of the National Academy of Sciences, a research team may have resolved why some blood vessels are able to grow to, and feed, tumors, while other vessels are not. Lead scientists Dr. Sal Pizzo and Tammy Moser found that the blood protein angiostatin, which is known to stop the growth of new blood vessels to tumors, works by depleting the chemical energy that blood vessel cells need to grow.

To do this, angiostatin latches on to and inhibits ATP synthase, an enzyme that provides chemical energy for the cell. Without that energy, blood vessels cannot grow to the site of a tumor, and without the nutrients supplied by blood, tumors cannot grow larger than a pinhead. Conversely, when unchecked by angiostatin, ATP synthase provides a generator of sorts to blood vessels so that they can survive in the atmosphere of cell death caused by cancer. Cancer researchers have long wondered how these vessels stay vigorous enough to continue to grow to and feed tumors.

The discovery was surprising, according to Pizzo, because ATP synthase had never before been found on the surface of endothelial cells, which are the cells that line blood vessels. In fact, ATP synthase has not been known to exist outside of a cell body. It has only been found within mitochondria, sac-like structures that act as a cell's chemical powerhouse.