A Child's Life
Volume 25 Number 2
Photo © Tyagan Miller
Mark Kelley is battling a clever, vicious, and resourceful enemy. This enemy quickly adapts to whatever weapons are employed against it, often taking young lives and leaving grieving families to cope with the loss.
The enemy is soft-tissue sarcoma, cancerous tumors that find ways around the chemical therapies meant to kill them. But Kelley, the Jonathan and Jennifer Simmons Professor of Pediatrics at the Indiana University School of Medicine, is taking a page from Sun Tzu's treatise. He has identified a weak point in the subcellular logistics of these tumors (and of similar brain and ovarian tumors) that holds promise for an indirect attack.
Over time, all cells suffer natural damage to their DNA, the material that contains the genetic code and is stored in cell nuclei. Since healthy DNA is crucial to the well-being and reproductive life of a cell, every cell has pathways by which DNA repairs are made on an ongoing basis. But researchers have noticed that the same DNA damage-repair mechanisms operate even in tumor cells targeted by chemotherapy. The targeted cells are able to undo some of the damage done by chemotherapy.
"We're looking at ways to imbalance that DNA repair," Kelley explains. "We want to trick cancer cells into not repairing the damage after chemotherapy."
Kelley's tactic is simple, based on the concession that direct attack is ineffective: If you cannot stop the enemy's bombing attack directly, then subvert the mechanic who maintains the bombers. In the case of soft-cell sarcoma, Kelley and his team looked at the four major pathways to DNA repair in mammalian cells and noticed a particular enzyme that was prominent in one of the pathways.
"We found that an enzyme called APE was elevated in a DNA repair pathway of soft tissue sarcoma, brain tumors, and ovarian tumors," Kelley says. "The higher the mortality rate from the tumors, the higher the level of APE seemed to be." Since the APE enzyme level correlates to a higher level of repair activity, it appears to be a vital ingredient in the repair process. If this enzyme could be attacked, Kelley reasoned, the repair pathway would be ineffective.
Identifying the target was an important step, but it is only the first. "Now that we have the target," says Kelley, "we have to learn how to block the repair in cancer cells without impairing that work in regular cells."
One plan would use gene therapy to introduce mutant APE-repair enzyme into cancerous cells. Following chemotherapy, the cell would continue its repair work, but the mutant APE enzyme would ensure failure in that pathway.
Other methods of targeting the pathway are also being weighed. "Our goal in coming years is to have clinical trials to block APE," Kelley says. "We do basic science and learn a lot from it. But we do the basic science while keeping an eye on clinical applications."
He cautions, though, that there are many steps between the laboratory and therapeutic use in the clinic. Even before all the laboratory and regulatory hurdles, there is the simple fact that cancer is a resourceful and stubborn enemy.
"Cancer is like a car on Second Avenue in Manhattan," Kelley says. "Block the street in front of it, and it simply detours around the block." He is hopeful that targeting the APE enzyme on a major repair pathway will be a precise enough target to do real damage. "If we're right about this, the cancer will be more like a car in a small town with only one street. Block the road in front, and it has nowhere to go."
The knowledge gained from the enzyme research may aid other therapeutic approaches as well. "If we can learn to make cancer cells more sensitive to chemotherapy, we may also find ways to make healthy cells less sensitive to chemotherapy," Kelley explains. Such an approach could prevent the hair loss, anemia, nausea, and other side-effects now common with chemotherapy.
Kelley came to IU in 1993 from Loyola University. Since 1995, he also has been associate director of the Herman B Wells Center for Pediatric Research. The center, founded in 1991, focuses research on pediatric diseases, reaching across disciplines at the School of Medicine. The center's motto§"connecting research with kids"§underscores the emphasis on translating laboratory findings into clinical applications that may save young lives.
"My challenge is to move our findings as fast as possible from the laboratory to the clinic," Kelley says. "I can't wait to get up and go to work each day."