Contact: Leonard N. Karp
215-575-3720
lkarp@philadelphiamedicine.com
August 25, 2006
For immediate release:
In this month’s edition:
- Nawal Khafaji, MD Named PIM Vice President; Lillian Higgins Named Director, PIM Institute of Education
- Jefferson Scientists Show "Miracle" Cancer Drug Gleevec Can be Toxic to the Heart
- Crozer-Keystone Physicians Offer Capsule Endoscopy: A Tiny Camera Providing Less Invasive, More Accurate Procedures
- Penn Researchers Discover "Remote Control" for Expression of Human Growth Hormone Gene Mistakes in Expression Implied in Growth Disorders.
Editors note: Research, new techniques and improved facilities by Philadelphia International Medicine hospitals and physicians may lead to new ways to treat some of our most challenging diseases. Below are just some examples from our hospitals.
Nawal Khafaji, MD Named PIM Vice President;
Lillian Higgins Named Director, PIM Institute of Education
Philadelphia – Nawal Khafaji, MD, has been named vice president of patient services at PIM, effective immediately, and will assume responsibility for all operational aspects of Philadelphia International Medicine services for international patients. Dr. Khafaji had been director of the Middle East Division at PIM since 2000.
In addition, Lillian Higgins was named director of the PIM Institute of Education, which conducts seminars and conferences for international physicians, including a monthly video conference seminar aired live and simultaneously to more than 22 sites around the globe. Ms. Higgins formerly was a project manager at the Society of Hospital Medicine, the professional medical society for hospitalists. There, she helped develop a core curriculum and training programs for the Society.
Dr. Khafaji has been responsible for expanding PIM programs and services throughout the Middle East, and will continue to oversee PIM efforts in this and other global regions. Ms. Higgins will focus on expanding PIM education and training programs. PIM offers visiting physician programs, seminars and conferences in Philadelphia and abroad, speakers for international conferences, residency programs for international physicians, observerships and many other programs.
To contact Dr. Khafaji, please email her at nkhafaji@philadelphiamedicine.com; Ms. Higgins, lhiggins@philadelphiamedicine.com.
Jefferson Scientists Show "Miracle" Cancer Drug Gleevec Can be Toxic to the Heart
Gleevec, the wildly successful poster-child of a new generation of cancer drugs aimed at specific targets in the cancer cell, can be dangerous to the heart. Not only that, but other similarly based drugs – called tyrosine kinase inhibitors – could lead to heart problems as well, say researchers at the Center for Translational Medicine at Jefferson Medical College in Philadelphia.
A team of scientists led by Thomas Force, MD, James C. Wilson Professor of Medicine at Jefferson Medical College of Thomas Jefferson University, has shown in studies in both mice and in heart cells in culture that Gleevec can cause heart failure. The results of the study, prompted by 10 patients with chronic myelogenous leukemia (CML) who developed severe congestive heart failure while taking Gleevec, appeared in an advanced online edition of the journal Nature Medicine.
"We found that the molecular target of the drug, the Abelson tyrosine kinase (ABL) protein, serves a maintenance function in cardiac muscle cells and is necessary for their health," Dr. Force explains. "While the cancer is treated effectively, there will be some percentage of patients who could experience significant left ventricular dysfunction and even heart failure from this."
"Gleevec is a wonderful drug and patients with these diseases need to be on it," he says. "We’re trying to call attention to the fact that Gleevec and other similar drugs coming along could have significant side effects on the heart and clinicians need to be aware of this. It’s a potential problem because the number of targeted agents is growing rapidly."
Gleevec is a new type of cancer drug – the first of its kind developed to fight cancer by turning off an enzyme that causes cells to become cancerous and multiply. In CML, an enzyme called ABL goes in overdrive because of a chromosomal mix-up that occurs during blood cell development. The genes ABL and BCR become fused and produce a hybrid BCR-ABL enzyme that is always active. The overactive BCR-ABL, in turn, drives the excessive proliferation of white blood cells that is the hallmark of CML.
According to Dr. Force, 10 patients taking Gleevec at the University of Texas’ M.D. Anderson Cancer Center in Houston developed fairly severe heart failure, with no prior symptoms. Because physicians there took baseline measures of the patients left ventricular heart function, the team was able to determine that heart failure developed in these patients between two and 14 months after beginning Gleevec.
The research team probed the potential mechanisms behind the drug’s possible toxic effects on the heart. Dr. Force explains that at the outset, the scientists couldn’t tell if the toxicity was from the drug’s effect on the known drug targets, or from an off-target effect or even a non-specific problem. "Sorting that out is important because then we can say, for example, if there are 10 more ABL inhibitors coming on line soon, and if the problem is really with inhibition of ABL, then these may have toxicity problems as well," he says.
The team proved that ABL was the guilty target by using viruses that coded for normal ABL and a Gleevec-resistant mutant. Gleevec inhibited the normal enzyme but not the mutant, and the mutant ABL "rescued" the heart cells from the toxic effects of Gleevec, proving that ABL is the relevant target. As a result, second-generation Gleevec drugs might also have similar toxicities in the heart.
"This finding is a big surprise and there may be a lot more of these," Dr. Force notes. "It’s not a class effect like COX-2 inhibitors. The drugs are all tyrosine kinase inhibitors, but each tyrosine kinase is different. It’s difficult to predict what tyrosine kinases will have protective roles in the heart and inhibition of them will be toxic."
Newer drugs tend to be ‘dirtier’ – that is, companies are developing drugs that hit multiple cancer cell targets at once to up the chances of effectiveness. Finding the exact target that, when inhibited, can cause problems with the heart, is critical to designing agents to counteract this effect.
In Gleevec, for example, blocking the PDGF receptor is crucial to its effect in thwarting gastrointestinal stromal tumors. Designing a drug to inhibit the PDGF receptor but not ABL, then, could still work against such tumors but not cause heart problems.
"We’ve learned something about the biology of the heart," Dr. Force says. "ABL is important for cardiomyocyte health. We also can learn something about how to stay away from these targets that are important and optimize the drugs."
In other studies, the researchers attempted to find the biological pathways involved in causing heart cells to die. They found that Gleevec appears to cause endoplasmic reticulum stress, which is initially a protective response by the cell, but if sustained, leads to cell death. They also found that treating mice heart cells with Gleevec led to the cells losing mitochondrial function, leading to cell death.
Jefferson, in collaboration with M.D. Anderson, the Cleveland Clinic and one or more European centers is planning to begin a registry for new tyrosine kinase inhibitors. "As these drugs come out, we can more easily collect data on larger numbers of patients as they take the drugs to get an idea of the incidence of heart problems," Dr. Force explains.
Dr. Force doesn’t think it’s possible to screen for potential heart problems that could be related to Gleevec. He notes that physicians involved in pre-release clinical trials of tyrosine kinase inhibitors will be aware of the potential problems and evaluate heart function if symptoms or signs possibly due to heart failure appear.
Crozer-Keystone Physicians Offer Capsule Endoscopy:
A Tiny Camera Providing Less Invasive, More Accurate Procedures
At any local electronics store, a wide variety of digital cameras are on display. Although many vary in capabilities, one common component in most of these cameras is their continually shrinking size. None of the cameras at the local electronics store, however, can match the tiny size of a camera that is making small intestinal endoscopy a much less invasive and more accurate procedure.
Capsule endoscopy, approved by the United States Food and Drug Administration in 2001, involves a vitamin-sized pill that contains a color camera, a battery, a light source and a transmitter. The camera takes two pictures every second for eight hours, transmitting images to a recording device worn by patients around their waists.
"This is a major advance in the imaging of the small intestine," says Immanuel Ho, M.D., chief of Gastroenterology at Crozer-Chester Medical Center, who began using capsule endoscopy in May for patients suffering from intestinal bleeding or intestinal disorders. "It can make an accurate diagnosis in minimal time with minimal discomfort to the patient. The technology is amazing and the pictures we get are incredible."
Previously, physicians had to rely on an endoscope - a thin tube with a camera on its tip that gets inserted into a sedated patient’s mouth and down through the esophagus and stomach into the small intestine – to attempt and find the cause of intestinal bleeding. This type of endoscope is invasive and does not provide a complete picture of the small intestines due to the complexity of maneuvering the tube through the turns of the small intestine.
With capsule endoscopy, the patient can swallow the pill and engage in normal activities throughout the day without discomfort, all while the camera takes pictures and makes its way through the digestive tract. After eight hours, the patient returns the recording device back to the physician. The camera exits the patient’s body naturally and is not retrieved.
"Capsule endoscopy gains access to the small intestine that is not reachable with the standard endoscope," says Mark Jacobs, MD, chief of Gastroenterology at Delaware County Memorial Hospital. "It allows us to see subtle causes of bleeding and diagnose Crohn’s disease."
Once returned to the physician’s office, the images from the device are downloaded to a computer, where the physician can evaluate the images and make a proper diagnosis.
"It’s a remarkable device. The patients bring the recorder back and we download it to the computer and burn it to a DVD," says Dr. Jacobs. "It takes maybe 45 minutes to an hour to review the DVD and make a diagnosis."
"The diagnostic yield is higher with capsule endoscopy," Dr. Ho says. "With a higher yield, we can find out a lot more about the small intestine and look for the causes of intestinal bleeding and chronic abdominal pain."
Dr. Ho says that in preparation for the capsule endoscopy, patients must not eat or drink anything the day before. Two hours after the patient swallows the pill, liquids are permitted, followed by solid foods two hours after that.
"As far as complications, there have been very rare cases of intestinal blockages, but no other real complications," Dr. Ho says. "Of course, if a person has problems swallowing, that can complicate it, in which case, we’d have to place the pill in the patient’s stomach."
Aside from determining the cause of intestinal bleeding, physicians can use capsule endoscopy to detect polyps, Crohn’s disease, ulcers and tumors in the small intestine.
"Capsule endoscopy has become the gold standard for minimally invasive detection of small bowel pathology," says Dr. Ho.
Penn Researchers Discover "Remote Control" for Expression of Human Growth Hormone Gene
Mistakes in Expression Implied in Growth Disorders
Researchers at the University of Pennsylvania School of Medicine recently discovered a novel mechanism that works over an extensive genomic distance and controls the expression of human growth hormone (hGH) in the pituitary gland. This mechanism involves a newly discovered set of "non-coding RNAs" expressed in the vicinity of the hGH gene.
By examining the relationship between these non-coding RNAs and the hGH gene, researchers hope to understand how these remote regions impact hGH gene expression and dysfunction. Such insight may aid researchers in the development of therapeutics for growth hormone defects and lead to a greater understanding of the causes of other genetic disorders.
The human genome is comprised of both non-coding DNA and coding regions, or genes. While researchers once believed that only genes were transcribed into messenger RNA (mRNA), investigators have recently discovered that non-coding DNA is copied into mRNA as well. Unlike coding mRNAs, which are translated into functional proteins and peptides, the function of most non-coding RNAs is unclear. Although non-coding RNAs fail to produce functional proteins, researchers believe that in some cases these RNAs may control gene expression.
Using a genetically modified mouse model, Nancy E. Cooke, MD, Stephen A. Liebhaber, MD, professors of Genetics and Medicine, and colleagues, demonstrated a critical role of two non-coding regions on the activation of the hGH gene. They described their recent findings in the August issue of Molecular Cell.
Synthesized by the pituitary gland, human growth hormone activates growth and cell reproduction. In addition to serving as a major contributor to height growth during childhood, hGH plays a role in strengthening bones and increasing muscle mass throughout life. While mutations to the hGH gene often lead to abnormal growth in children and adults, these mutations have provided researchers with key clues regarding the genomic areas that appear to control expression of the hGH gene.
Previous work in the laboratories of Drs. Cooke and Liebhaber found that the hGH gene is controlled by a non-coding DNA region, or locus control region. Remarkably, this region is located more than 14,000 base pairs away from the hGH gene. At the genomic level, a 14,000 base-pair separation is equal to the size of 10 growth hormone genes lined end to end. "The effects of the locus control region on human growth hormone expression is as if you turn a key in the lock of a house at one end of your street and find that this action opens the lock and door of a house a block away," notes Dr. Liebhaber.
By carefully analyzing the 14,000 base pairs separating the hGH gene and its locus control region, co-authors Yugong Ho, PhD, an instructor of Genetics at Penn and a Cooke/Liebhaber lab member, and Felice Elefant, PhD, assistant professor at Drexel University and former member of the Cooke/Liebhaber lab, found that the locus control region was copied into RNA, and discovered a gene called CD79b within this region. Remarkably this CD79b gene was also copied into RNA in the pituitary. While the CD79b gene normally codes for a protein in blood lymphocytes, researchers discovered that CD79b appears to play a very different role in the pituitary gland. Here, CD79b was actively transcribed into mRNA, but this mRNA failed to translate into a functional protein. Instead, the non-coding RNA was suspected to play a role in hGH gene regulation.
In order to determine whether the CD79b RNA in the pituitary gland served a function, Dr. Ho inserted a segment of human DNA that included hGH, the hGH locus control region, and CD79b into a group of mice. As a result, the transgenic mice expressed high levels of human growth hormone in the pituitary as well as mouse growth hormone. To test whether the transcription of the locus control region and CD79b played a significant role in hGH expression in transgenic mice, Dr. Ho then inserted a special piece of DNA into the locus control region. This DNA insertion specifically blocked the copying of the CD79b gene into RNA in the pituitary. This blockade led to the five-fold repression of hGH gene expression. These findings confirm that the CD79b non-coding DNA actively contributes to hGH expression. The relationship between CD79b, the hGH locus control region, and the hGH gene may aid researchers in the development of treatments for patients suffering from hGH deficiency.
"Our data predict that a subset of children with short stature and low growth hormone may be suffering from a mutation in the hGH locus control region, which blocks full levels of hGH gene activity," explains Dr. Ho. "We are now actively screening the appropriate clinical populations for such genetic defects."
In the future, Drs. Cooke, Liebhaber and Ho will continue to search for how transcription contributes to long-range activation of hGH gene expression through the development of new transgenic mouse models and the biochemical analysis of the hGH locus.
"By understanding how non-coding DNA functions at the human growth hormone locus, researchers may be able to identify similar situations at other genetic loci," says Dr. Liebhaber.
"With every step forward in understanding how genes are expressed, we increase our awareness of how naturally occurring and acquired mutations interfere with this process," adds Dr. Cooke. "Our research sets the groundwork for advances in diagnosis and eventual treatment of genetic diseases."
These studies were funded by the National Institutes of Health. Penn Medicine is a $2.9 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System.
Penn’s School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #3 in the nation in U.S. News & World Report’s most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.