Quick formula could forecast which cancers chemo could kill

Jul 15 2008

Researchers at the University of Rochester Medical Center have coined a simple formula that predicts how well a certain chemotherapy will work for targeting brain and other nervous system cancers. The formula, which publishes mid-July in Cancer Chemotherapy and Pharmacology, is pegged to two important proteins that compose such hard-to-kill tumors - one of which, ironically, makes them so drug-resistant in the first place.

"We're unraveling the mysterious, even paradoxical, ways chemotherapies interact with various cancers," said one of the study's investigators Nina F. Schor, M.D., Ph.D., the William H. Eilinger professor and chair of the department of Pediatrics at Rochester. "From this, we're developing techniques that will help us more quickly predict which medicines are most effective for each tumor."

Schor is an expert in neuroblastoma, a childhood cancer of the peripheral nervous system that usually manifests in the chest or abdomen. Her team, like many others nationwide, is in hot pursuit of forecasting tools that pave the way for more personalized "matching" of treatments to tumors. Such practices would not only mean more effective and gentler chemotherapy in the short term, but also that survivors would wrestle fewer and less severe side effects in later life.

"Since nervous system cancers are the most common solid tumors in childhood - with brain tumors affecting almost one in 10,000 kids and neuroblastoma affecting one in 100,000 kids - this work has significant future implications for children battling these cancers," Schor said.

While the particular drug studied, neocarzinostantin (NCS), works remarkably well for brain tumors and other nervous system cancers in the lab - even when other frontline treatments fail - it's been shown to trigger severe allergic reactions in people and is not FDA-approved. Even so, Schor and her colleagues are hopeful that its mechanisms may provide a sort of roadmap for developing similar synthetic, safer drugs, especially since the part of the NCS molecule blamed for allergic reactions is unconnected to its chemotherapeutic power.

How, exactly, was this formula born? Schor's team knew that stubborn tumors evaded chemotherapy because of an over-abundance of Bcl-2, a protein that hampers apoptosis, or programmed cell death. Despite its grim sound, such cell death is actually is a helpful tool, renewing the body's pool of cells and acting as the body's own scheduled maintenance system, not unlike getting seasonal oil-changes for a car or replacing the batteries in a smoke detector.

Thankfully, another protein, called caspase-3 and nicknamed an "executioner protein" for its role in inducing cell death, exists in many of these same tumors. And Schor's team had a hunch that the NCS drug was activating these executioner proteins to slice off a section of the vexing Bcl-2 protein - a tiny but critical snip that effectively converted Bcl-2 from a protein that inhibited cell death to a protein that promoted it.

"Here was a paradox - the same protein first blamed for making tumors super resistant was being altered to cooperate with chemotherapy and help weaken them," Schor said. "Our formula grows out of this idea that if these two key proteins are abundant in tumors, that information alone tells us that NCS can kill those cancers."

Their formula proved reliable. After measuring these two critical proteins in each of four cancer types - three nervous system cancers (glioma, neuroblastoma and medulloblastoma) and a breast cancer - the team treated each with NCS to test its effect. As expected, the cells with the highest concentrations of both Bcl-2 and caspase-3 proteins were also most sensitive to the drug. Even tiny amounts of the chemotherapy were enough to kill them quickly.

"Clearly, the way our body works with medicines is not always intuitive," Schor said. "We have to piece together puzzles. We have to begin asking how these chemotherapies find ways to overcome resistance, because increasingly, this understanding will help us predict which medicines will best help which patients."

Schor and her team are now turning their attention to honing NCS's cell-killing power so that the drug can better distinguish between tumors and healthy tissue. She said that until this drug or ones like it are approved for use in clinical trials, parents of children with cancer should participate in Children's Oncology Group therapeutic protocols, which not only make the best new treatments available to them, but offer the satisfaction of helping to shape tomorrow's medicine. The University of Rochester Medical Centers' Golisano Children's Hospital participates as member of the Children's Oncology Group.

This research was possible thanks to funding by the National Cancer Institute and the National Institute of Neurological Diseases and Stroke, and the collaboration of Rochester investigators Danny Rogers, Zhiping Mi, M.D., and Tong Hu, Ph.D., along with Karen Nylander, R.N., of the University and Children's Hospital of Pittsburgh.