Studying DNA Repair to Treat Pediatric Cancer & Tackle the Side Effects of Treatment
For kids with certain kinds of cancer, the survival rates just keep getting better. But some researchers aren’t satisfied with the status quo, and rightfully so. Even the most effective cancer therapies cause a range of side effects, from permanent cognitive damage to neuropathies that cause pain and tingling in the limbs.
“While we have some good treatments in place for a number of pediatric cancers, they aren’t perfect,” says Mark R. Kelley, PhD, a scientist at the Herman B Wells Center for Pediatric Research. “We also need to do better with reducing the side effects, and that’s one of our initiatives.”
Kelley is considered a national leader in an area of study known as DNA repair—a field pioneered by three scientists who earned the 2015 Nobel Prize in chemistry for their groundbreaking discoveries, now linked to many healthcare advances.
These concepts have long been of interest to Kelley, who has made a career of learning about the pathways that repair DNA. To that end, Kelley has experimented for decades with numerous models such as fruit flies, mice and finally, with human samples donated for research by children treated at Riley Hospital for Children at IU Health. At the Wells Center, he and his team follow a passion, hoping their work may lead to information that can not only treat some forms of pediatric cancer, but also reduce side effects from treatment.
Their current work aims to identify DNA pathways and understand how they are altered in various pediatric cancers. Their targets include neuroblastoma (usually found in the adrenal glands), osteosarcoma (a common bone cancer), glioblastoma (fast-growing brain tumors) and a form of neurofibromatosis (NF1) called MPNST (Malignant Peripheral Nerve Sheath Tumors).
It is becoming very clear that targeting just one pathway has limited effectiveness. Researchers and clinicians now believe they must strike multiple targets at once to outsmart tumor cells. This is the approach Kelley and his colleagues are taking. His research team has identified multiple pathways for study, including those that are crucial for tumor cell growth.
As those studies continue, they are also exploring a promising new area of research that could improve life for children who are treated with harsh chemotherapy drugs. Specifically, they want to interrupt side effects such as chemotherapy-induced peripheral neuropathy (CIPN) and brain damage resulting in cognitive problems, commonly called chemo-brain or brain-fog. Unfortunately, there are no FDA-approved drugs to combat CIPN.
“The reason there are no good treatments or preventions for CIPN is that we don’t fully understand the underlying mechanisms of how and why neurons that control feeling and activity in your fingers and toes are affected by some of these agents,” Kelley says. “If we understand how these agents work on the neurons differently than the way they work on a tumor, we can learn how to block the negative effect.”
Unlocking those secrets could go even further by reversing damage after the fact. “We are excited because we have discovered that DNA damage from several cancer treatments appear to work through a DNA repair pathway we focus on—DNA base excision repair (BER),” he says. This knowledge will help Kelley’s team and other collaborators stay focused on finding ways to block and reverse DNA damage to prevent CIPN.
As someone who is part of a sea change in cancer treatment, Kelley makes a compelling case for basic science. Together, he and his team at the Wells Center identified a protein that interrupts the growth of certain pancreatic cancers—the fourth leading cause of death from cancer.
How does pancreatic cancer relate to pediatric cancer? Well, some of the same pathways and proteins altered in pancreatic cancer are also good targets in kid’s cancers, a focus of study for Kelley, his research team and other collaborators.
In 2016 they hope to get FDA approval on a Phase I clinical trial for a drug that is based on their discovery. The drug protects against CIPN in cell and animal models, potentially making way for treatment of tumors while preventing CIPN.
Once initial clinical studies for safety are done, they want to apply that knowledge to pediatric cancers. “Basic research and bench science is the foundation of all progress,” he says. “Without it, we are just taking a blind shot in the dark, and you can’t just guess at how these pathways are changed.”
Kelley emphasizes the role of philanthropy as he travels, often speaking to Indiana high school and college students who support research through fundraising dance marathons on behalf of Riley Children’s Foundation. “I tell young people that we need their nickels, dimes and quarters now more than ever,” Kelley says. “We’re doing some really great science that can help us be smarter about how we target certain kinds of cancer, but we’re up against some very difficult odds.”
By some estimates, only 8 percent of all grant applications to the National Institutes of Health (NIH) are funded. Despite all the promising ideas now in the pipeline, some may sit idle because today’s national research budget is nearly the same as it was 12 years ago, according to Kelley. “If you look at any new treatment to move detection, prevention or treatment, it takes decades,” he says. “That’s one of the reasons that funding for research is so important.”
Fortunately, the Wells Center has been very successful at overcoming those odds by maintaining a steady flow of ideas that intrigue donors and grant funders. In 2015, for example, scientists at the Wells Center received NIH support for a national research project that will convert basic science discoveries to treatments for various life-threatening tumors that affect children.
