Targeted therapy combo overcomes treatment resistance in liver cancer

Apr 13 2008

Researchers at the University of Pennsylvania School of Medicine and Abramson Cancer Center reported at the annual meeting of the American Association for Cancer Research that combining two targeted therapies overcomes treatment resistance in liver cancer cell lines.

The team is currently designing a trial to test the combination in patients.

Liver cancer is resistant to many chemotherapies and to cell-death inducing agents. Last year, however, the U.S. Food and Drug Administration approved sorafenib (Nexavar®) as a treatment for liver cancer after a clinical trial showed that the targeted agent prolonged survival in some patients. Unfortunately not all patients respond to sorafenib and the drug does not cure the disease.

Therefore, Wafik El-Deiry, MD, PhD, Professor of Medicine, Genetics, and Pharmacology, and co-Program Leader of Radiation Biology in the Abramson Cancer Center, and colleagues have tested other targeted agents in combination with sorafenib.

They found that treating liver cancer cells with sorafenib and an antibody or the natural ligand that stimulates programmed cell death via the TRAIL pathway, dramatically increases the rate of cell death.

“Sorafenib by itself causes a little cell death, but not that much,” Dr. El-Deiry said. “Now you combine sorafenib and TRAIL, and all of the sudden you get massive cell death. It is a real synergistic interaction. It is very profound killing.”

The combination works regardless of whether the researchers use a monoclonal antibody that stimulates the TRAIL receptor, which resides on the surface of the cancer cells, or the receptor's natural ligand, a small protein called TRAIL. Both the antibody and the TRAIL ligand are currently being tested as single agents in patients.

Within the next several months, Dr. El-Deiry's team expects to announce the details for a trial testing the combination in patients.

In a healthy individual, the immune system uses the TRAIL pathway to rid the body of unwanted cells, including precancerous ones. Once cancer develops, however, the cells often become less responsive to TRAIL activation, in part because of an overabundance of a protein called Mcl-1, according to Dr. El-Deiry. His team found that sorafenib reduces the amount of Mcl-1 in the cancer cells, restoring their sensitivity to TRAIL-induced cell death.

Although the Penn investigators focused their current report on liver cancer, they discovered that the sorafenib-TRAIL combination also kills colon cancer cell in vitro and in animal models.

The current work was supported by grants from the National Cancer Institute and the American Association for Cancer Research.

Source:
AACR abstract #833
“Sorafenib sensitizes hepatocellular carcinoma cells to TRAIL or TRAIL receptor agonist antibodies” Junaid Abdulghani, Patrick A. Mayes, David T. Dicker, Charles D. Smith, Robin C. Humphreys, Wafik S. El Deiry. University of Pennsylvania, Philadelphia, PA, Medical University of Southern Carolina, Charleston, SC, Human Genome Sciences, Rockville, MD.

PENN Medicine is a $3.5 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in 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 currently ranked #4 in the nation in U.S. News & World Report's survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. 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.The University of Pennsylvania Health System includes three hospitals — its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation's “Honor Roll” hospitals by U.S. News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center — a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.

The Abramson Cancer Center (ACC) of the University of Pennsylvania is a national leader in cancer research, patient care, and education. The pre-eminent position of the Cancer Center is reflected in its continuous designation as a Comprehensive Cancer Center by the National Cancer Institute for 30 years, one of 39 such Centers in the United States. The ACC is dedicated to innovative and compassionate cancer care. The clinical program, comprised of a dedicated staff of physicians, nurse practitioners, nurses, social workers, physical therapists, nutritionists and patient support specialists, currently sees over 50,000 outpatient visits, 3400 inpatient admissions, and provides over 25,000 chemotherapy treatments, and more than 65,000 radiation treatments annually. Not only is the ACC dedicated to providing state-of-the-art cancer care, the latest forms of cancer prevention, diagnosis, and treatment are available to our patients through clinical themes that developed in the relentless pursuit to eliminate the pain and suffering from cancer. In addition, the ACC is home to the 300 research scientists who work relentlessly to determine the pathogenesis of cancer. Together, the faculty is committed to improving the prevention, diagnosis and treatment of cancer.