Although doctors and scientists have made significant strides in treating childhood cancer, there are still too many children experiencing tumors that don’t respond to therapy, spread to other parts of the body or come back later.
V Scholar Adam Shlien, PhD, from the Genetics & Genome Biology Program at SickKids and the Department of Laboratory Medicine and Pathobiology at the University of Toronto has devoted his career to finding better ways to fight these aggressive pediatric cancers so that more kids can go on to live long and healthy lives. His current work focuses on cancer “fingerprints”—the thousands of genetic mutations that are unique to an individual tumor. Studying these mutational fingerprints can reveal how a tumor arose or why it came back, information that is already leading to new treatment strategies.
“Rather than studying cancer in a dish or in the lab, we learn from the tumors themselves by using patient samples to study the critical pathways that drive cancer development,” said Shlien. “The patterns of mutational signatures can tell us what caused the cancer, when the mutations occurred and, sometimes, which treatments might work for an individual patient.”
Building the right team
Mutational signatures are a relatively new area of cancer research that came about thanks to advances in DNA sequencing technology and new computational techniques for analyzing the huge amounts of data produced by sequencing.
V Foundation support helped Shlien build the type of multidisciplinary team necessary to conduct this type of work. The team includes people with backgrounds in machine learning, statistics, computation and computer science, who he then trained in cancer biology. “It can be tough to recruit these types of experts because we’re in competition with tech companies, but, once brought into the team, they can have a massive impact in our understanding of pediatric cancer,” said Shlien.
Bringing their biology and technology expertise together, the researchers developed a computational pipeline to genetically analyze tumor tissue from hundreds of children who are patients at SickKids. Their algorithms crunch vast amounts of data to analyze a variety of tumor types at different time points to see how mutational signatures change over time.
“We aren’t just looking at a small number of genes—we are sequencing the DNA of the entire tumor genome and transcriptome,” said Shlien. “The Precision Child Health initiative at SickKids has given us the ability to broadly look for patterns by enrolling a large number of patients. Every patient teaches us something new.”
Through the V Foundation project, the researchers created a catalog of mutational signatures in childhood cancer and identified which signatures are most clinically important. They are now using their analytical processes and research findings to help patients who are currently being treated for cancer at SickKids.
For example, their work has revealed important similarities between some childhood cancers and breast and ovarian cancers caused by mutations in the BRCA1 or BRCA2 genes. “We knew that mutations in this pathway were present but weren’t sure that they were truly driving the childhood cancers,” said Shlien. “However, when we looked at the mutational signatures, we could see that the pathway affected by the BRCA mutation was dysfunctional. We’ve already seen some positive responses from giving childhood cancer patients similar PARP inhibitors that have been used to treat BRCA-related cancers in adults.”
The researchers are also studying associations between certain chemotherapy drugs and mutational signatures. These signatures might offer a way to figure out, early in the treatment process, which patients might be resistant to a specific therapy.
Fighting cancer is a team effort, and Shlien says sharing data with other doctors and researchers is an important part of his team’s ethos. In addition to sharing raw data such as DNA sequencing results, the team has developed tools that help translate their findings into information that can be used to directly help patients.
“It is our responsibility to learn as much as we can from every child who develops cancer and enrolls in one of these programs,” Shlien said. “Sharing data is the only way to make sure that any insight we derive from their tumor can help subsequent patients.”
[expandable topic=”Using technology to improve health”]Shlien was interested in the intersection between technology and health from an early age. “I was one of those kids who learned how to program and would take apart all the electronics in the house,” he recalls. “My mom tells me that she has a note I wrote in grade eight that said I wanted to be a cancer researcher.”
A high school science project further cemented his interest in cancer. For the project, Shlien micro-dissected a sample of a lung tumor he acquired with help from his mother, who worked at a hospital. “When the whole genomics revolution exploded [a few years later], it made me excited to find out how bioinformatics and computational expertise could be used to find even more insights into cancer,” he said. [/expandable]