Novel Target for Drug May Improve Effectiveness of Radiation Therapy

Scientists have found a new drug target that could improve the effectiveness of radiation for hard-to-treat cancers.

The study's findings, published online August 20, 2010, in the Journal of the National Cancer Institute, focuses on the role of the enzyme cytosolic phospholipase A2 (cPLA2). This enzyme promotes development and functioning of blood vessel networks that feed malignant tumors, enabling them to overcome the effects of radiation. They have also identified a drug that blocks production of the enzyme. Inhibiting the enzyme can stop the flow of blood tumors need to survive.

Tumors thrive and spread due to a unique ability to recruit networks of new blood vessels that penetrate into tumors, bringing oxygen, nutrients,and potentially transporting cancer cells to other areas of the body. Cancer cells trigger the process of new blood vessel construction, called angiogenesis, by releasing specific molecules into surrounding normal tissue, initiating a cascade of molecular signals that cause cells lining existing blood vessels to divide and create new vessels. These new vessel networks link the tumor to the circulatory system and its life-sustaining cargo.

Lung cancer and glioblastoma, the most common type of primary brain tumor, are particularly skillful at inducing new blood vessel creation via angiogenesis. They are also highly resistant to treatment by radiation. "Our original objective was to measure the signaling molecules that enable lung and brain cancer to be resistant to radiation,” noted Dennis Hallahan, M.D., a professor of medicine and chair of the department of radiation oncology at Washington University School of Medicine in St. Louis (MO, USA) and senior author of the study. "There are hundreds of signaling molecules, but the enzyme cPLA2 stood out,” Dr. Hallahan stated. "Radiation of tumor cells triggers production of cPLA2 within two minutes and it contributes to tumor survival.”

The cPLA2 enzyme is known to regulate the levels of at last three molecules that promote tumor angiogenesis (the creation of new blood vessel networks to feed cancer cells). The researchers set out to learn if they could enhance the effect of radiation therapy for lung and brain cancers by inhibiting this enzyme. The plan was to implant tumors into normal mice and into mice that had been genetically engineered to be unable to produce cPLA2 and then compare the effect of radiation therapy on tumor progression in each.

The enormous power of cPLA2 became apparent to Dr. Hallahan when a graduate student complained that her experiment failed because she could not grow tumors in mice that lacked the gene that produces cPLA2. "While implanted tumors progressed as expected in normal mice used in the experiment, they were virtually undetectable in cPLA2-deficient mice,” Dr. Hallahan stated. "The ‘failed experiment' was actually a significant discovery of the enormous control cPLA2 has in regulating tumor angiogenesis.”

The scientists then studied the blood vessels of the cPLA2-deficient mice. Whereas the blood vessels of cPLA2-deficient mice appeared normal, close inspection revealed the absence of a specific type of contractile cell that regulates blood flow. "Without these cells, blood vessels can still grow into the tumor but blood cannot flow to the tumor,” Dr. Hallahan stated. "Cancer cannot survive without blood flow to feed it.”

The essential role of cPLA2 in determining the presence or absence of these contractile cells makes it a prime target for interventional therapy. "Drugs that target cPLA2 have enormous potential for improving the success of radiation against highly angiogenic tumors,” Dr. Hallahan said.

Dr. Hallahan has already identified an existing drug that inhibits cPLA2. It is a compound originally developed by Wyeth (Madison, NJ, USA), now part of Pfizer (New York, NY, USA), as a treatment for arthritis. The drug had advanced to phase II testing before being discontinued as a potential arthritis treatment. Reaching phase II testing, however, suggests that a compound has been proven safe, regardless of whether or not it meets performance standards for the specific medical condition for which it was made. These drugs are typically then tested for other uses.

Dr. Hallahan learned of the Pfizer compound from a partnership between Pfizer and Washington University that allows Washington University scientists to evaluate extensive research data on a large range of Pfizer pharmaceutical candidates that are or were in clinical testing.

Don Frail, Ph.D., chief scientific officer of Pfizer's Indication's Discovery Unit, reported that most of drug candidates tested in development do not give the desired result. "Yet those drugs that do succeed typically have multiple uses,” Dr. Frail said. "Hallahan's research has led to an entirely new potential use for one of these compounds in an area of high patient need that otherwise might have been overlooked. This is exactly what our partnership with Washington University is about and is among the first to be funded through the new relationship.”

Dr. Hallahan is currently collaborating with Craig Wegner, Ph.D., in the Indications Discovery Unit of Pfizer to understand further the pathways impacted by cPLA2 and to assess the drug that suppresses its action.

Related Links:
Washington University School of Medicine in St. Louis
Pfizer