Penn researchers identify new combination therapy that promotes cancer cell death

Philadelphia -- Researchers at the University of Pennsylvania School of Medicine identified a combination therapy as a way to sensitize resistant human cancer cells to a treatment currently being tested in clinical trials They propose that the therapy may help to selectively eliminate cancer cells while leaving healthy cells intact, providing a cancer treatment with fewer side effects. The Penn team reports their findings in the July issue of Cancer Cell.

To test the ability of the combined therapy in treating cancerous tumors, senior author Wafik S. El-Deiry, MD, PhD, and colleagues administered TRAIL, a tumor necrosis factor, and sorafenib, an inhibitor currently used to treat renal cancer, to mice with colon carcinomas. The sorafenib and TRAIL therapy reduced the size of tumors in mice with few side effects, demonstrating the potential effectiveness of the combined treatment on human colon cancers.

"Cancer cells will do whatever it takes to survive in harsh environments," explains El-Deiry, Professor of Medicine, Genetics, and Pharmacology. To kill hearty cancer cells, El-Deiry and other scientists are working on ways to alter them so they become more susceptible to cell death.

In ongoing clinical trials, doctors are giving cancer patients extra doses of TRAIL (TNF-a-related apoptosis-inducing ligand), a molecule naturally produced by the body's immune system that promotes cell death, to help kill off cancer cells. While TRAIL-based therapy is promising, over 50 percent of all cancer cells show resistance to TRAIL. To create a more potent form of targeted cancer therapy, El-Deiry's research team began searching for ways to reverse TRAIL resistance in cancer cells.

Recently, El-Deiry's research group found that TRAIL-resistant cells avoid death by producing 'survival' proteins called cIAP2 and Mcl-1. The oncogene c-Myc in part hampers a cancer cell's survival strategy by blocking the function of an intermediate protein that oversees cIAP2 and Mcl-1 production. Without these survival proteins, cancer cells are unable to resist the death initiated by TRAIL.

In search of drugs that perform a similar cancer-cell death function to c-Myc, El-Deiry's lab turned to sorafenib, which is also being considered for the treatment of a variety of cancers. Like c-Myc, the researchers found that sorafenib blocked the intermediate and survival proteins when combined with TRAIL, causing TRAIL-resistant colon and lung cancer cell lines to die.

"Our findings are exciting because TRAIL in combination with sorafenib appears to be much less toxic than current chemotherapy drugs," explains El-Deiry. "Plus, sorafenib is already available in a pill form."¨

While enthusiastic about his recent findings, El-Deiry notes sorafenib may be working to increase cell sensitivity to TRAIL through more biochemical pathways than the intermediate alone.

"The ability of sorafenib to work through multiple pathways may be beneficial to cancer treatments because cancer may be altering multiple targets," says El-Deiry.

In the future, El-Deiry plans to explore additional pathways sorafenib may be working through to increase TRAIL sensitivity and to compare the effectiveness of other drugs.

"In addition to proposing a combination therapy that's rational, non-toxic, and effective in preclinical trials, our findings open up new avenues of molecular exploration for designing targeted anti-cancer therapies," said El-Deiry.

Source: University of Pennsylvania School of Medicine

Related stories:

On the trail of a targeted therapy for blood cancers
Investigators from the Herman B Wells Center for Pediatric Research at the Indiana University School of Medicine are focusing on a family of blood proteins that they hope holds a key to decreasing the toxic effects of chemotherapy in children and adults.
Researchers find targeted therapy combination overcomes treatment resistance in liver cancer
Researchers at the University of Pennsylvania School of Medicine and Abramson Cancer Center reported today 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.
Novel strategy under study for aggressive leukemia
A novel strategy to hopefully beat into oblivion one of the most aggressive forms of acute myelogenous leukemia combines the strengths of some of the newest leukemia agents, researchers say.
Laser blasts viruses in blood
A father-son research team working from separate laboratory benches across the country has discovered a new use for lasers - zapping viruses out of blood. The technique, which holds promise for disinfecting blood for transfusions, uses a low-power laser beam with a pulse lasting just fractions of a second.
Ancient Genetic Material Keeps Pups Pint-Sized
Soon after humans began domesticating dogs 12,000 to 15,000 years ago, they started breeding small canines. Now, scientists from the University of Utah and seven other institutions have identified a piece of doggy DNA that reduces the activity of a growth gene, ensuring that small breeds stay small.
Researchers hot on the trail of brain cell degeneration
A research team headed by Academy Research Fellow Michael Courtney has identified a new molecular pathway in neurons. The pathway is a factor in the degeneration of brain cells, which in turn plays an important role in neurological conditions and diseases, such as Alzheimer's disease, epilepsy and stroke.
Cancer-killing invention also harvests stem cells
Associate Professor Michael King of the University of Rochester Biomedical Engineering Department has invented a device that filters the blood for cancer and stem cells. When he captures cancer cells, he kills them. When he captures stem cells, he harvests them for later use in tissue engineering, bone marrow transplants, and other applications that treat human disease and improve health.
Scientists find cancer cell defense method
A Seoul, South Korea, research team says it's identified the defense mechanism used by cancer cells to fight therapeutic chemicals.

News discussion:

Medicine & Health news