PHILADELPHIA INTERNATIONAL MEDICINE® NEWS BUREAU
Contact: Leonard N. Karp
lkarp@philadelphiamedicine.com
215-735-3989
June 27, 2005

For immediate release:

In this month's issue:

1. Report Says New Focus Needed to Produce New Drugs for Children with Cancer
2. Jefferson Researcher’s Results Show Promise for Metastatic Eye Melanoma
3. “Laser Tweezers” Permits Penn Researchers to Describe Microscopic Mechanical Properties of Blood Clots

Editors note: Research by Philadelphia International Medicine physicians may lead to new ways to treat some of our most challenging diseases. Below are some examples from our hospitals.

Report Says New Focus Needed to Produce New Drugs for Children with Cancer

Philadelphia – Market forces alone are not sufficient to produce new drugs needed for children with cancer, according to a new report by the Institute of Medicine (IOM) that was edited by a pediatric oncologist at The Children’s Hospital of Philadelphia. Faced with “a near absence of research in pediatric cancer drug discovery,” the IOM report recommends forming new public-private partnerships among government, industry, researchers, advocacy groups and other parties to lead research and development.

The report, “Making Better Drugs for Children with Cancer,” analyzes childhood cancer treatment in the light of historic advances. “Over the past 40 years, researchers and clinicians have achieved long-term survival for most children and adolescents with cancer,” said pediatric oncologist Peter C. Adamson, MD, chief of the division of clinical pharmacology and therapeutics at The Children’s Hospital of Philadelphia, and an editor of the report. “However, our therapies are not curative for 30 percent of children, and for children who are cured, the short-term and long-term side effects of current treatments are often too high.”

Dr. Adamson is a member of the IOM’s Committee on Shortening the Time Line for New Cancer Treatments, which issued the report. As chair of the developmental therapeutics program of the Children’s Oncology Group, a nationwide consortium of pediatric oncology centers, Dr. Adamson took a leadership role in drafting the report. The Institute of Medicine is part of the National Academy of Sciences, a private, nonprofit organization of scholars chartered by the U.S. Congress.

The absolute number of U.S. children with cancer is relatively small (about 12,000 cases diagnosed annually, compared to 200,000 new cases of breast cancer alone), and pharmaceutical companies do not consider it profitable to invest in research and development for pediatric cancer drugs. Oncologists have used many existing adult cancer drugs to treat children, but many of those drugs have toxic side effects. On the other hand, say the authors, some new drugs being developed for adult cancers may still prove useful for children with less common cancers.

“The major childhood cancers are often distinct from adult cancers at the level of molecular abnormalities, and more focused research and development might allow us to better target those abnormalities,” said Dr. Adamson. “More targeted drugs might not only allow us to better attack the most difficult childhood cancers, but also cause fewer toxic side effects, by sparing healthy cells.”

The IOM report says that select components of a pediatric drug pipeline already exist in academic medical centers, industry, universities, and in federal centers such as the National Cancer Institute. Those resources include repositories of synthetic and natural products, services to screen compounds for anticancer activity, drug discovery databases, and programs to support drug assays and clinical trials.

“What is needed is a comprehensive mechanism to put all these pieces together into a pediatric drug pipeline,” says Dr. Adamson, emphasizing one of the major recommendations of the IOM report. The IOM proposes a partnership among government, industry and academia to produce new pediatric anticancer drugs. It suggests that in cases where companies do not proceed to full development of promising pediatric drugs, the federally sponsored National Cancer Institute should assume responsibility as the developer of last resort.

As one model of a public-private partnership focused on a health condition, the IOM report describes the Therapeutics Development Program established by the Cystic Fibrosis Foundation to support the research and development of new drugs for cystic fibrosis. That program, begun in 1997, has forged agreements with government and industry to form a “virtual” research and development pipeline.

In addition to proposing a coordinated pediatric oncology drug pipeline, the IOM proposes to speed up the drug development process by setting priorities to determine which pediatric drugs should be tested among the limited pool of children with cancer. It also recommends initiating pediatric trials earlier than they typically begin.

About the Oncology Program at The Children’s Hospital of Philadelphia: The Children’s Hospital of Philadelphia cares for more children with cancer than any other general pediatric hospital in the United States. Its extensive basic and clinical research programs have been recognized recently by Child Magazine, which ranked Children’s Hospital first in the nation in pediatric oncology.

Jefferson Researcher’s Results Show Promise for Metastatic Eye Melanoma

When melanoma of the eye spreads to the liver, patients have few good options. Surgery is frequently impossible, and chemotherapy hasn’t proven effective. But now, by simultaneously revving up the immune system and choking off the tumor’s oxygen supply, oncologists at Jefferson Medical College and the Kimmel Cancer Center at Thomas Jefferson University in Philadelphia may have found a better way to battle this deadly cancer.

Researchers, led by Takami Sato, MD, K. Hasumi Associate Professor of Medicine at Jefferson Medical College of Thomas Jefferson University, have shown promising results from an early, phase 1-2 clinical trial of a novel treatment for uveal melanoma that has spread to the liver.

In the procedure, called immunoembolization, Dr. Sato and his co-workers “embolize,” or block off the hepatic artery, which is a major artery feeding the liver, cutting off oxygen to liver tumors. They infuse a chemical called GM-CSF, which stimulates the immune system – specifically, cells called macrophages and dendritic cells – to produce an inflammatory reaction, and it’s hoped, fight the cancer.

In the trial, which was aimed at testing for treatment toxicity and feasibility, Dr. Sato found that 30 percent of 39 patients studied (34 of whom had uveal melanoma) had tumor shrinkage and another 30 percent had tumors that didn’t grow.

“We have seen a surprising phenomenon,” he says. “Compared to chemoembolization (a similar, older therapy that entails giving a patient chemotherapy directly into the liver), our patients did just as well and some did better. The treatment is doing something to prolong survival.

“If we’re right,” Dr. Sato says, “we could delay metastases.”

Dr. Sato also found a response in other tumors in the body besides the liver – a potentially important finding, he says. Patients in the study lived on average about twice as long compared to those who received chemoembolization in an earlier study he and his team conducted.

Dr. Sato heads one of the few programs in the nation treating metastatic uveal melanoma, which is a melanoma originating in the eye and the most common adult eye tumor. It is very rare, affecting perhaps 6 or 7 individuals per 1 million. When it spreads to the liver, patients who do not receive treatment live on average about 6 months. The treatment Dr. Sato is testing is used for patients who are not eligible for surgery.

While the trial results show the two-pronged treatment is safe and feasible – as well as providing promising responses to metastases, Dr. Sato reaffirms the need for a larger phase 2 study, which has already opened for patients with uveal melanoma metastatic to the liver. The phase 2 trial compares immunoembolization to embolization, or cutting off the tumor’s oxygen supply. The trial is funded by an R21 grant for nearly $600,000 over two years that he recently received from the National Cancer Institute.

In the new trial, he will also monitor the immune system reaction, looking for an increase in numbers of specific immune cells. He plans to biopsy patient livers, he notes, because “ If the GM-CSF is working, an inflammatory response should be seen in the liver tumor.”

The next step in the future, he says, would be to conduct a phase 3 multicenter trial comparing chemoembolization and immunoembolization. He notes that the immunoembolization procedure may be useful in treating primary liver cancer or other types of cancer that have spread to the liver as well.

“Laser Tweezers” Permits Penn Researchers to Describe Microscopic Mechanical Properties of Blood Clots

For the first time ever, using “laser tweezers,” the mechanical properties of an individual fiber in a blood clot have been determined by researchers at the University of Pennsylvania School of Medicine. Their work, led by John W. Weisel, PhD, professor of cell and developmental biology at Penn, and published in this week’s early online edition of the Proceedings of the National Academy of Sciences, provides a basis for understanding how the elasticity of the whole clot arises.

Clots are a three-dimensional network of fibrin fibers, stabilized by another protein called factor XIIIa. A blood clot needs to have the right degree of stiffness and plasticity to stem the flow of blood when tissue is damaged, yet be digestible enough by enzymes in the blood so that it does not block blood-flow and cause heart attacks and strokes.

Weisel and colleagues developed a novel way to measure the elasticity of individual fibrin fibers in clots-with and without the factor XIIIa stabilization. They used “laser tweezers”-essentially a laser-beam focused on a microscopic bead ‘handle’ attached to the fibers-to pull in different directions on the fiber.
The investigators found that the fibers, which are long and very thin, bend much more easily than they stretch, suggesting that clots deform in flowing blood or under other stresses primarily by the bending of their fibers.

Weisel likens the structure of a clot composed of fibrin fibers to a microscopic version of a bridge and its many struts. “Knowing the mechanical properties of each strut, an engineer can extrapolate the properties of the entire bridge,” he explains. “To measure the stiffness of a fiber, we used light to apply a tiny force to it and observed it bend in a light microscope, just as an engineer would measure the stiffness of a beam on a macroscopic scale. The mechanical properties of blood clots have been measured for many years, so now we can develop models to relate individual fiber and whole clot properties to understand mechanisms that can yield clots that have vastly different properties.”

He states that these findings have relevance for many areas: materials science, polymer chemistry, biophysics, protein biochemistry, and hematology. “We present the first determination of the microscopic mechanical properties of any polymer of this sort,” says Weisel. “What’s more, our choice of the fibrin clot has particular biological and clinical significance, since fibrin’s mechanical properties are essential for its functions in clotting and also are largely responsible for the pathology of thrombosis that causes most heart attacks and strokes.”

By understanding the microscopic mechanical properties of a clot and how that relates to its observed function within the circulatory system, researchers may be able to make predictions about clot physiology. For example, when clots are not stiff enough, problems with bleeding arise, and when clots are too stiff, there may be problems with thrombosis, which results when clots block the flow of blood.

But how can this knowledge be used to stop bleeding or too much clotting?

“Once we understand the origin of the mechanical properties, it will be possible to modulate those properties,” explains Weisel. “If we can change a certain parameter perhaps we can make a clot that’s more or less stiff.” For example, various peptides or proteins, such as antibodies, bind specifically to fibrin, affecting clot structure. The idea would be to use such compounds in people to alter the properties of the clot, so it can be less obstructive and more easily dissolved.
“This paper shows how new technology has made possible a simple but elegant approach to determine the microscopic properties of a fibrin fiber, providing a basis for understanding the origin of clot elasticity, which has been a mystery for more than 50 years,” adds Weisel.

Weisel’s Penn co-authors are Jean-Philippe Collet, Henry Shuman, Robert E. Ledger, and Seungtaek Lee. Funding for the study was provided by the National Institutes of Health, Assistance Publique Hopitaux de Paris, and Parke-Davis.

Philadelphia International Medicine is an organization that provides medical and patient support services to international patients. It also provides continuing medical education and health care training and education to international physicians, administrators and other practitioners. As the international department of several Philadelphia-area hospitals, international patients gain access to physicians and hospitals rated among the best in the world through one telephone call to PIM. You can reach PIM by calling 1-215-735-3575; fax, 1-215-790-1267; or e-mail, physicians@philadelphiamedicine.com . You can find out more about PIM through its Website at www.philadelphiamedicine.com .