PHILADELPHIA INTERNATIONAL MEDICINE® NEWS BUREAU
Contact: Leonard N. Karp
lkarp@philadelphiamedicine.com
215-735-3989
April 22, 2005

For immediate release:

In this month's issue:

1. Penn Researchers Determine Structure of Binding Site of Colon-Cancer Drug and Its Protein Target
2. Children’s Hospital Identifies Abnormal Brain Tissue Associated with Perception Problems
3. Temple’s New Knee Replacement Procedure and Implant Offer Longer Lasting Results

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.

Penn Researchers Determine Structure of Binding Site of Colon-Cancer Drug and Its Protein Target

Philadelphia – Researchers at the University of Pennsylvania School of Medicine have determined the precise molecular details of how Erbitux, a recently approved colorectal cancer drug, binds to its target on cancer cells. Knowing this chemical configuration will lead to better drug design for this family of cancer medications.

Colorectal cancer is one of the most frequently diagnosed cancers in men and women, as well as the second-leading cause of cancer-related death, according to the Centers for Disease Control and Prevention. Erbitux works by binding to a protein on the surface of cancer cells, thereby halting excessive cell growth that leads to tumors. Kate Ferguson, PhD, assistant professor of Physiology, and colleagues, describe their findings in the April cover article of Cancer Cell.

“By having determined the structure of Erbitux bound to its cellular target receptor, we get new insight into how the drug blocks the receptor’s cell growth-promoting activities, and can use this to guide future drug design,” says Dr. Ferguson.

As is characteristic of many epithelial cancers - such as cancers of the head and neck, breast, ovary, lung, and pancreas - the surface of cancer cells possess abnormally high levels of epidermal growth factor receptor (EGFR), the protein that interacts with Erbitux. These receptors are made up of three parts: one outside the cell; another passing through the cell membrane; and the third inside the cell. In a cancer cell, an extracellular hormone binds to the outer piece of EGFR, and causes the inside part to kick off a series of reactions that signal the cancerous cell to replicate and divide.

Dr. Ferguson and colleagues determined that Erbitux works to halt cell proliferation by blocking EGFR’s molecular doorway, disallowing hormones to bind and signal tumor growth. X-ray crystallography provided a snapshot of the interaction between Erbitux and the extracellular component of the cancer cell’s receptors.

The resulting structural information deciphered by Dr. Ferguson and colleagues emphasizes the importance of drug research targeting active protein receptors on cancer cells and tumors. As is the case in Erbitux, “the protein EGFR needs to not only be present on tumors but it needs to be there and be active,” says Dr. Ferguson.

“Understanding the structure could help us design alternatives to Erbitux that would be easier to deliver in small-molecule medications to be taken as a pill,” as opposed to the current intravenous administration of the drug, Dr. Ferguson adds. The researchers’ hope is that with these new insights into Erbitux’s action and structure, treatments for colorectal cancer and other epithelial cancers will be expanded, thereby contributing to the creation of future generations of improved cancer drugs.

The study was funded by the National Institutes of Health, the Burroughs Wellcome Fund, and ImClone Systems Inc. Study co-authors Paul Kussie and Jed. J.W. Wiltzius are employees of ImClone, the manufacturer of Erbitux. Shiqing Li and Karl R. Schmitz from Penn, and Philip D. Jeffrey (formerly from the Memorial Sloan-Kettering Cancer Center and now Princeton University) are also co-authors. The authors report no conflicts of interest related to this research.

Children’s Hospital Identifies Abnormal Brain Tissue Associated with Perception Problems

Certain genetic diseases affect children’s educational abilities in a distinctive pattern: impairing their numerical abilities more than their verbal skills? New research sheds light on this split in abilities by investigating how differences in brain structures may influence how the mind works.

Researchers at The Children’s Hospital of Philadelphia, studying a common chromosome disorder, have used high-tech imaging tools to identify abnormal brain tissue associated with problems in perceiving spatial relationships and thinking about numbers.
Understanding the links between brain structure and brain function may offer clues to improving methods to help children with specific learning disabilities. By pinpointing specific sites in the brain associated with impaired mental functions, scientists hope to eventually help children retrain their brains to follow alternative pathways and work around their cognitive weaknesses.

Cognitive neuroscientist Tony J. Simon, PhD, led the studies of children with chromosome 22q11.2 deletion syndrome, the most common genetic deletion syndrome. In this disorder, a tiny portion of chromosome 22 is missing, causing symptoms such as heart defects, cleft palate, abnormal immune responses and cognitive impairments. Children’s Hospital is a world center for research and treatment of the syndrome.

The current work draws on cognitive neuroscience - an emerging scientific field that investigates how the mind arises from the biology of the brain. One important factor driving the field is the application of tools such as magnetic resonance imaging (MRI) to yield more precise measurements of structures in the living brain. MRI can provide images and compute volumes of anatomical features. In addition, by measuring how water diffuses in the brain, it indicates the layout of nerve fibers and suggests how brain areas are connected to each other.

Dr. Simon is now at the M.I.N.D. Institute of the University of California, Davis. He recently published two studies of patients at The Children’s Hospital of Philadelphia with chromosome 22q11.2 deletion syndrome. One study, in the April 2005 issue of Cortex, measures impairments in the children’s visual-spatial and numerical skills. A complementary study, in the March issue of NeuroImage, describes structural abnormalities in the brains of children with the syndrome. The abnormal structures occurred in and around the posterior parietal lobe, toward the back of the brain.

“Together, these studies strengthen our hypothesis that abnormalities in the brain’s parietal lobe are a critical factor in the visual-spatial and numerical processing difficulties that we see in children with this syndrome,” said Dr. Simon.

Researchers have known for some time that children with chromosome 22q11.2 deletion syndrome perform poorly in math skills compared to verbal skills. The current research provides evidence toward an explanation of that gap in cognitive abilities.
In the Cortex study, the Children’s Hospital team compared 12 children with the syndrome to 15 healthy children. They found children with the chromosome deletion performed more poorly on experiments designed to test visual attention orienting, enumerating, and judging numerical magnitudes. All three tasks relate to how the children mentally represent objects and the spatial relationships among them. In previous research, Dr. Simon has argued that such visual-spatial skills are a fundamental foundation to the later learning of counting and mathematics.

“Studies in adults have shown that damage to the posterior parietal lobe impairs a person’s visual-spatial and numerical thinking,” said Dr. Simon. “These findings strengthen the evidence for a similar relationship in children.”

The study in NeuroImage compared 18 children with the deletion to 18 healthy children. Using MRI techniques, the research team used newer methods to confirm previous findings of reductions in posterior brain volume and in grey and white matter. But the researchers also found something new: changes in the shape, size and position of the corpus callosum, a structure that connects the brain’s two hemispheres.

“It may be that the basic problem lies in how parts of the brain are connected,” said Dr. Simon. “It’s like having a fuzzy signal on your cell phone - the phone is working, but the connections are defective.”

Chromosome 22q11.2 deletion syndrome is one of the most common genetic sources of developmental disability. “The population of children with chromosome 22q11.2 deletion syndrome is growing, as improved heart care allows many more children to survive the heart defects that commonly occur in the condition,” said clinical geneticist Elaine H. Zackai, MD, a co-author of both studies and medical director of the 22q and You Clinic at Children’s Hospital.

The findings may have implications for other diseases as well. “Chromosome 22q11.2 deletion syndrome is one of a number of conditions with a similar pattern of visual-spatial and numerical impairments, grouped as nonverbal learning disabilities,” said Dr. Simon. “It may turn out that all these conditions have common changes to critical pathways in the brain. As we gain greater understanding of the details of how neural circuits are connected for particular brain functions, we can design strategies for therapies, because children’s brains are more plastic than adult brains, and more capable of reconfiguring tasks through alternative paths,” added Dr. Simon. “Our findings represent early steps toward that goal.”

The National Institutes of Health and the Philadelphia Foundation provided funding for both studies. Dr. Simon’s co-authors on the Cortex study were Carrie Bearden, PhD, Donna McDonald-McGinn, MS, C.G.C., and Elaine Zackai, MD, of Children’s Hospital. His co-authors on the NeuroImage study were Lijun Ding, Joel P. Bish, Ms. McDonald-McGinn, and Dr. Zackai, of Children’s Hospital; and James Gee, MD, of the University of Pennsylvania.

The Children’s Hospital of Philadelphia houses the 22q and You Center, the largest program in the world specializing in chromosome 22q11.2 deletion syndrome. The multidisciplinary center provides care for children needing specialists in medical genetics, cardiology, plastic surgery, immunology, endocrinology and neurology. In the early 1980s, geneticists at Children’s Hospital were among the researchers that identified deletions in chromosome 22 as responsible for the syndrome, and later developed a diagnostic test for the syndrome that is now used around the world. With sponsorship from the National Institutes of Health, researches from Children’s Hospital produced a map of chromosome 22 in 1995, and in 1999, collaborated with the Human Genome Project in publishing the sequence of chromosome 22, the first human chromosome to be sequenced under that Project.

Temple’s New Knee Replacement Procedure and Implant Offer Longer Lasting Results

Orthopedic surgeons at Temple University Hospital are now performing minimally invasive knee replacements with the assistance of a computer and a new “rotating platform” knee joint. The new procedure, together with the new technology, offers knee replacement patients better function and longer-lasting results.

A computer-guided navigational system in the operating room allows Temple surgeons to place knee joints with far greater accuracy than the traditional method, which uses surgical cutting dyes and positions by eye.

“The use of the computer-guided navigational system allows us to position the implants within a half-degree of rotation and one millimeter of desired placement,” says William DeLong, MD, co-director of the Temple Orthopedic Trauma Service. “This level of precision is not possible when you are relying on the human eye for placement.”

The Ci computer system, which was developed by DePuy Orthopedics, Inc., provides a 3-D rendering of the joint. On-screen bone-morphed imaging accurately represents the individual patient’s anatomy. Alignment and positioning can be checked and fine-tuned at every stage of the procedure.

“The technology allows us to see in advance exactly what the cuts are going to look like and then we can make the most precise adjustments,” says Dr. DeLong.

Putting implants in the best possible position can be expected to support a longer life for them. “Positioning the implant in the normal access of the limb allows it to function with minimal friction and wear,” says Dr. DeLong.

At Temple, many knee replacement procedures are done minimally invasively. Small incisions mean quicker recovery for the patient, but in the past they also made precise placement of the new joint challenging. “When you make small incisions, reference points are not as easy to see, so placement is often not as accurate as it might be with an open procedure,” says Dr. DeLong.

With the new computer technology, the minimally invasive procedure is also the most accurate surgical procedure. “With the computer-guided system, we can use smaller incisions with certainty that the joint is being placed in precisely the right position,” says Dr. DeLong.

Temple orthopedic surgeons are using the computer-guided system to implant a new type of replacement knee, called the “rotating platform” knee. Unlike the traditional fixed-bearing knee, the rotating-platform knee allows for more rotation, making it suitable for more active people. A polyethylene insert allows the tibia and femoral parts of the knee to move more smoothly, mimicking the natural motion of a healthy knee joint.

“This reduces friction and wear on the implant,” says Dr. DeLong. “The theoretical advantage shown in biomechanical testing suggests that there is 90 percent less wear when you use a rotating platform implant. That means it could last up to 25 years.”

Patients may not notice a significant difference in mobility using a rotating platform implant versus a fixed implant. However, studies have shown some improvements in bending ability. “Although we don’t have 20-year follow-up studies, it does seem as though this improvement will revolutionize knee replacement,” says Dr. DeLong. “Since people are living longer and have more active lives, this type of implant will be the standard choice for many people in the future.”

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 .