Goal is to learn how aberrant fusion proteins turn healthy cells into tumor cells
A cancer researcher at Nationwide Children’s Hospital has received a federal five-year, $6.2 million grant to help uncover how proteins produced by a mutated gene transform healthy cells into tumor cells.
The National Cancer Institute at the National Institutes of Health announced it has awarded one of its Cancer Moonshot grants to Stephen Lessnick, MD, PhD, director of the Center for Childhood Cancer and Blood Diseases at The Research Institute at Nationwide Children’s.
Dr. Lessnick, who is also a professor of pediatrics at The Ohio State University College of Medicine, is part of a national consortium of researchers investigating fusion oncoproteins.
While most adult cancers result from a combination of multiple mutations, most childhood cancers contain a limited number of mutations. In fact, the cancer Dr. Lessnik’s lab studies, Ewing sarcoma, is triggered by a single mutation that produces the fusion oncoprotein called EWS/FLI.
“Fusion oncoproteins are master regulators,” he says. In the case of Ewing sarcoma, “one fusion protein does it all to produce cancer.”
But how remains the question.
EWS/FLI is produced by a specific type of mutation, called a translocation, involving two chromosomes that have been broken and rejoin abnormally. This abnormal rejoining causes a fusion of portions of the EWS and FLI genes, thus creating the EWS/FLI fusion oncoprotein.
Dr. Lessnick and colleagues have found EWS/FLI binds to unusual DNA sequences and regulates genes around them. “It turns thousands of genes on and off and in doing so accomplishes all the things needed for cancer to develop,” Dr. Lessnick says. “This massive change in gene regulation leads to Ewing sarcoma.”
The Cancer Moonshot program articulated a goal of increasing research in pediatric cancer and recognizes that many pediatric cancers are caused by fusions, including gene regulators like EWS/FLI. “When we got all the experts together in a room to discuss how to attack the problem of fusion oncoproteins, we recognized that we don’t really know how they work,” Dr. Lessnick says. “We need to understand how they work in order to know how to go about blocking them.”
The NIH’s goal is to fund a team of scientists with enough diverse expertise to understand fusion oncoprotiens and how to target them in the clinic.
Dr. Lessnick is teaming with Xavier Darzacq and Robert Tijan, at the University of California, Berkeley, to learn how EWS/FLI interacts with a DNA sequence scattered throughout the human genome: GGAA microsatellites. These microsatellites were once considered “junk” DNA that did nothing.
“It turns out, by an incredible stroke of bad luck, EWS/FLI uses this ‘junk’ DNA to regulate genes required for Ewing sarcoma development,” Dr. Lessnick says.
Dr. Lessnick will work with the Richard Wilson, PhD, director of the Institute for Genomic Medicine at Nationwide Children’s, and Elaine Mardis, PhD, co-director of the Institute, to define the specific DNA EWS/FLI attaches to and where it is located in the genome.
Dr. Darzacq has developed new microscopy techniques that investigators believe will enable them to see how the protein binds to DNA and turns on and off genes.
“We hope to describe the process in the detail needed for investigators to develop a new therapy,” Dr. Lessnick says.