Contact: Leonard N. Karp
215-575-3720
lkarp@philadelphiamedicine.com
June 26, 2007
For immediate release:
In this month’s edition:
- Fox Chase Doctors Conclude Temsirolimus Is an Effective New Treatment for Patients With Advanced Renal Cell Carcinoma
- Penn Researchers Link Cell’s Protein Recycling Systems; Implications for Treating Neurodegenerative Disorders
- Pancreatic Surgery Riskier for Obese Patients, Jefferson Surgeon Finds
- ‘Nondanger’ Signal Lowers Immune Reactions; May Be Used to Blunt Transplant Rejection, Autoimmune Diseases
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.
Fox Chase Doctors Conclude Temsirolimus Is an Effective New Treatment
for Patients With Advanced Renal Cell Carcinoma
Philadelphia – The results of a phase III, randomized clinical study involving patients with advanced renal cell carcinoma and poor prognostic features show temsirolimus improved overall survival when compared to the current treatment for this stage of disease. The study, led by Gary R. Hudes, MD, director of the Genitourinary Malignancies Program at Fox Chase Cancer Center, was published in the May 31 issue of the New England Journal of Medicine.
A total of 626 patients with renal cell carcinoma (RCC) were enrolled in the study and received one of three treatments – a new drug called temsirolimus, an older drug called interferon, or both the new and old drugs together. The patients who received temsirolimus alone survived longer than those who received interferon, the usual or ‘standard’ treatment for this disease.
"This is the first study to show that a new drug can improve overall survival for patients with metastatic renal cell cancer," said Dr. Hudes.
Patients who received both drugs - temsirolimus and interferon - did not appear to live longer than those given interferon. Hudes said this finding could be explained by the lower dose of temsirolimus given to patients who received the combination treatment.
Renal cell carcinoma (RCC) is the most common type of kidney cancer. Approximately 90 percent of the 51,190 new cases of kidney cancer diagnosed this year will be RCC. Although many patients with kidney cancer are cured by surgery that removes the tumor, approximately 35 percent of patients will experience a recurrence of their cancer or will have spread (metastasis) of their cancer to other organs.
"For these patients, the goal of treatment is to prevent further spread and growth of the cancer, and ideally, to reduce that amount of cancer," Dr. Hudes said. "Until recently, physicians lacked effective drugs to control the disease."
In the current study, the greatest increase in median survival was observed in patients randomized to receive temsirolimus (49 percent) compared with patients treated with interferon only. Patients treated with temsirolimus and interferon combined had a 15 percent increase in median survival compared with interferon alone. The median survival for temsirolimus alone was 10.9 months compared with and 8.4 months for the temsirolimus and interferon, and 7.3 months for the interferon.
"This is a modest improvement in survival but the patients in the study had the most advanced tumors," says Dr. Hudes. "It would be reasonable to hypothesize that temsirolimus could provide greater benefit to patients with less extensive metastatic disease. Only a randomized, clinical trial will give us that definitive knowledge."
Temsirolimus was better tolerated than interferon. Fewer patients treated with temsirolimus had grade 3 or 4 (severe) side effects compared with those treated with interferon or the combination of interferon and temsirolimus. Asthenia, anemia, nausea, dyspnea, and rash were the most common side effects associated with temsirolimus.
Temsirolimus (formerly known as CCI-779) blocks the function of the mammalian target of rapamycin (mTOR), a key protein within cells that regulates cell proliferation, growth and survival. Temsirolimus may also block angiogenesis, a process that tumors use to create a blood supply to maintain their growth.
On May 30, 2007, the U.S. Food and Drug Administration (FDA) approved TORISEL™ (temsirolimus) for patients with advanced renal cell carcinoma (RCC).
Penn Researchers Link Cell’s Protein Recycling Systems; Implications for
Treating Neurodegenerative Disorders
Many age-related neurological diseases are associated with defective proteins accumulating in nerve cells, suggesting that the cell’s normal disposal mechanisms are not operating correctly. Now, researchers at the University of Pennsylvania Medical Center have discovered a molecular link between the cell’s two major pathways for breaking down proteins and have succeeded in using this link to rescue neurodegenerative diseases in a simple animal model. The study appeared recently in Nature.
The cell has two internal pathways for breaking down proteins. The ubiquitin-proteasome pathway marks unwanted proteins with ubiquitin tags and shuttles them for rapid breakdown to a complicated structure called the proteasome. The second is the autophagy-lysosomal system, a more general process in which proteins are surrounded by membranes inside the cell for bulk digestion.
"The dogma has been that the autophagy-lysosomal and the proteasomal systems are trains that run on different tracks, with similar purposes, but no point of intersection," explains senior author J. Paul Taylor, MD, PhD, assistant professor of Neurology. "The new finding directly challenges this thinking by showing that one system can be induced to compensate for the other. Cells are able to shift proteins between the systems. We think that this molecular link can be used to benefit a wide variety of neurodegenerative diseases because accumulation of toxic proteins is a common underlying feature of age-related neurodegeneration."
Dr. Taylor and his group study fruit flies in which the proteasome is disabled by a genetic mutation, which results in neurodegeneration. They use the fly eye, a neuron-rich tissue, as a surrogate for the brain because it is easy to visualize. They discovered that making the lysosomal system more or less active dramatically influenced the severity of neurodegeneration.
"We found that whenever we knocked the lysosome system down, neurodegeneration always got worse," says Dr. Taylor. "Then when we activated the autophagy system by feeding the flies a drug called rapamycin, neurodegeneration was prevented." The accumulated misfolded proteins were cleared out by the lysosome system. "Then we knew that this system can compensate for the impaired proteasome function, which in itself tells us that the two pathways intersect," said Dr. Taylor. "The question was, ‘How is this working?’"
"That’s where the power of fruit flies comes in," Dr. Taylor explained. "We can use fruit flies to rapidly screen through many genes to find the one we’re interested in. In the process of screening, our attention was drawn to HDAC6 because we already knew that it could bind to ubiquitin-tagged proteins and transport them within the cell. So we wondered, could HDAC6 be the link?"
Dr. Taylor’s group showed that if the HDAC6 gene is knocked out, inducing autophagy no longer rescues the fly eyes from neurodegeneration. Therefore, autophagy requires HDAC6 to work. They also showed that by simply expressing extra HDAC6, neurodegeneration was prevented in flies with proteasome impairment. Dr. Taylor’s group then moved on to fly models of human neurodegenerative disease and showed that they, too, are rescued by over-expression of HDAC6.
Therefore, the researchers suggest that the level of the HDAC6 in a cell regulates its sensitivity to accumulation of misfolded proteins, and that increasing the activity of HDAC6 can prevent the degeneration normally associated with accumulating old, damaged proteins. The researchers suggest further that when proteasomes are impaired or overwhelmed, which leads to accumulation of defective proteins, HDAC6 facilitates delivery to the autophagy-lysosomal system for degradation. "That’s how we think HDAC6 links the two systems," said Dr. Taylor.
Dr. Taylor and his team are now testing the ability of HDAC6 to prevent neurodegeneration in several mouse models, including motor neuron disease, Parkinson’s disease, and Huntington’s disease. They are also attempting to identify pharmacologic approaches to augmenting HDAC6 activity.
Penn co-authors are Udai Bhan Pandey, Zhiping Nie, Brett A. McCray, Gillian P. Ritson, Natalia B. Nedelsky, and Stephanie Schwartz.
This work was funded by the Kennedy’s Disease Association, the Morton Reich Research Fund, and the National Institute of Neurological Disorders and Stroke.
Pancreatic Surgery Riskier for Obese Patients, Jefferson Surgeon Finds
Obesity may contribute to a greater likelihood of post-operative complications for patients having pancreatic surgery, a surgeon at Thomas Jefferson University Hospital has found. A study of 202 pancreatic surgeries from 2000 to 2005 indicates obese patients had an increased time on the operating table, blood loss, length of hospital stay and rate of serious complications compared to normal weight individuals, said Adam Berger, MD, assistant professor of surgery at Jefferson Medical College of Thomas Jefferson University.
"A rise in a patient’s Body Mass Index (BMI) is one of the most important health issues facing health care professionals today," Dr. Berger noted. "Higher BMI can lead to a greater risk of a patient developing diabetes and heart disease, as well as esophageal and pancreatic cancers. Increased BMI has been demonstrated to be an important factor predicting perioperative morbidity and mortality in patients undergoing numerous operations."
At the time of surgeries, 85 (46 percent) patients were normal weight, 54 (29 percent) were overweight and 45 (25 percent) were obese, the study indicates. There were four perioperative patient deaths (2 percent), two of which were in the normal weight group and two in the obese group. In addition, obese patients had an increased rate of serious complications compared to normal and overweight patients (27 percent vs. 18 percent and 15 percent, respectively).
Nearly half the patients underwent a classic Whipple procedure, in which the gallbladder, common bile duct, lower part of the stomach, all of the duodenum (the first part of the small intestine) and the head of the pancreas are removed. Others underwent a pylorus-preserving pancreaticoduodenectomy, in which the head of the pancreas is removed.
"Obese patients are at higher risk for perioperative complications, however, this should not preclude them from having pancreatic surgery," Dr. Berger noted.
‘Nondanger’ Signal Lowers Immune Reactions; May Be
Used to Blunt Transplant Rejection, Autoimmune Diseases
Rheumatology researchers have discovered that a well-known cell receptor sends a signal to dampen the immune system. While not having an immediate application to treating disease, the finding raises the possibility that by targeting that receptor, physicians could stimulate a "nondanger" signal to rein in overzealous human immune responses. Controlling those responses could potentially protect transplant patients from rejection episodes or could relieve symptoms of autoimmune diseases such as rheumatoid arthritis and lupus.
The study, which was performed in mice, appeared in a recent issue of the Journal of Immunology.
Researchers from The Children’s Hospital of Philadelphia and The University of Pennsylvania reported that complement receptor 3 (CR3), a protein found on cell surfaces, inhibits dendritic cells, the sentinels of the immune system, from setting off an alarm signal that brings on a full immune response.
"Normally, dendritic cells patrol different tissues and organs and look for danger signals sent by tissues undergoing stress or responding to invading microorganisms," said Stefania Gallucci, MD, leader of the study team at The Children’s Hospital of Philadelphia. "We found that when we stimulate CR3 on dendritic cells, CR3 sends a ‘nondanger’ signal that suppresses the ability of dendritic cells to set off an immune response," added Dr. Gallucci, who is also an assistant professor at the University of Pennsylvania.
In their study, the researchers used a monoclonal antibody, engineered to bind to CR3, to trigger a cascade of responses that had a net result of decreasing the activation of T cells that would normally be produced. Tcells are immune cells that fight infection while contributing to the inflammation seen in an immune response.
"What is exciting about our research is that we have a new agent for modifying dendritic cell function," said pediatric rheumatologist Edward M. Behrens, MD, the first author of the study. "The monoclonal antibody we used is already in a form that can be used for further studies. It has anti- inflammatory effects, so it may be a potential weapon against inflammatory diseases."
One such disease is lupus erythematosus, an autoimmune disease in children and adults that may damage many organs. A next step, said Dr. Gallucci, is to test the antibody in mice that have a disease similar to lupus in humans. The study team also expects to test the antibody in animal models of rheumatoid arthritis. In addition, the researchers may investigate a possible role for the antibody as an immunosuppressant, in preventing a patient’s immune system from rejecting cell and organ transplants.
The National Institutes of Health, the Lupus Foundation Southeastern Pennsylvania Chapter and the Arthritis Foundation supported the study. Co-authors with Drs. Gallucci and Behrens, all from Children’s Hospital and the University of Pennsylvania School of Medicine, were Terri H. Finkel, MD, PhD; Uma Sriram, PhD; Debra K. Shivers; and Zhengyu Ma, PhD. Marcello Gallucci, PhD, of the University of Milano-Bicocca in Italy also was a co-author.
The Children’s Hospital of Philadelphia was founded in 1855 as the nation’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children’s Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country, ranking third in National Institutes of Health funding. In addition, its unique family-centered care and public service programs have brought the 430-bed hospital recognition as a leading advocate for children and adolescents.