Pediatric oncology researchers at The Children’s Hospital of Philadelphia are driven to find new treatments for childhood cancer, and the Hyundai Hope On Wheels program is supporting their hard work by awarding a 2014 Scholar Hope grant to help fund investigations that focus on the aggressive form of neuroblastoma. Despite intense treatment, more than 50 percent of children with high-risk neuroblastoma die of their disease, accounting for 12 percent of pediatric cancer deaths.
Kristina Cole, MD, PhD, a CHOP attending physician and researcher with expertise in identifying therapeutic targets in pediatric cancer, received the Scholar Hope grant at a “Handprint Ceremony” in front of the hospital Sept. 11. Children from the oncology floor were invited to place their handprints in paint on a Hyundai car that is traveling across the country to build awareness of pediatric cancer research. Hyundai Motor America and its more than 820 U.S. Hyundai dealers have donated more than $86 million to pediatric cancer research in the U.S. through Hope On Wheels.
Each child’s handprint stands out as one of a kind, as does Dr. Cole’s novel research project which aims to demonstrate, for the first time, that a subset of patients with neuroblastoma could benefit from checkpoint inhibition and support further clinical development of new generation checkpoint inhibitors for pediatric solid tumors.
In previous work, Dr. Cole and colleagues have shown that neuroblastoma tumors rely on the DNA repair checkpoint protein kinase 1 (CHK1) to handle the cellular stress caused by the powerful MYCN oncogene that drives tumor growth. When CHK1 is inhibited, the neuroblastoma cells can no longer grow and die. Several clinical trials are underway based on the idea that if cancer cells are exposed to a CHK1 inhibitor, the protein will be unable to respond when the cell’s DNA is damaged by treatments such as chemotherapy.
“This current research is unique because we’re trying to better understand which patients may benefit and why they may benefit,” Dr. Cole said. “We think that MYCN certainly has a very large role, but is it possible that other factors — like underlying defects in genes that mediate DNA damage — make certain patients even more likely to benefit from this treatment strategy.”
First, researchers will analyze large genomic datasets from hundreds of primary tumor samples to find any defects in DNA repair genes. Then, they will characterize how those mutations could make neuroblastoma tumors more sensitive than other tumor types to drugs that inhibit CHK1. Their third aim will be to do preclinical work in the laboratory with cell cultures and animal models to be able to justify a clinical trial of next generation checkpoint inhibitors in combination with traditional chemotherapy.
The researchers’ hypothesis that certain neuroblastoma tumors have increased dependency on the compensatory DNA repair pathway due to a possible defect in DNA repair genes is reminiscent of what has been described in breast cancer research, Dr. Cole said. Breast tumor cells with inherent DNA repair defects, such as mutations in BRCA1 or BRCA2, are sensitive to drugs that inhibit PARP, another protein that helps cancer cells repair DNA damage and survive. Tumor cells with normal BRCA proteins continue to grow.
Dr. Cole is among 36 Scholar Hope two-year grant winners, who each received $250,000 for a total of $9 million in support. The ultimate goal of the Scholar Hope grant program is to find cures for childhood cancers once and for all, according to the program’s website.
“It is a great award that they’ve put together to support the work done by individuals from Children’s Oncology Group institutions all across the country who are investigating pediatric cancers,” Dr. Cole said. “They’ve been very generous to CHOP.”