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VOL. 128 | NO. 70 | Wednesday, April 10, 2013

Time Recognizes St. Jude Genome Project

By Jennifer Johnson Backer

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In February, St. Jude Children’s Research Hospital completed a three-year-effort to sequence the genomes of 700 pediatric cancer tumors. It’s the largest project of its kind in the world.

DOWNING

While many of the discoveries won’t lead to immediate changes in the treatment of certain types of pediatric cancers, the research provides a map to begin exploring how to better treat patients with aggressive childhood cancers, says Dr. James Downing, the scientific director of St. Jude Children’s Research Hospital.

“When we started the project, I had many sleepless nights because it was such a major challenge to initiate the project,” he said. “But I also worried; would we make the discoveries that would really change the way we think about pediatric cancers? Would they give us insights that would ultimately help us better treat those patients?”

Downing, who was recently nominated by Time Magazine for its list of the 100 Most Influential People in the World, says he’s been surprised by the findings from each tumor the Pediatric Cancer Genome Project has mapped. Ultimately, the genome sequencing project has led to groundbreaking discoveries in some of the most aggressive childhood cancers.

The $65 million Pediatric Cancer Genome Project began in February 2010 at a time when only a single pediatric cancer genome had ever been completely sequenced. About $55 million of the overall funding came directly from St. Jude. A large federal government project, The Cancer Genome Atlas, was sequencing the genomes of adult cancers, but very little money and effort was going toward sequencing the genomes of pediatric cancers.

“Part of it was that we felt it was the responsibility of St. Jude, and that no one else would really step up to do this project,” Downing said. “We also know that there are children dying every day, so we felt a sense of urgency to try to get this accomplished as quickly as possible.”

At first, Downing and other researchers at St. Jude weren’t sure if a project of this magnitude was feasible. In 2007, they published a paper on the molecular genetics of Acute Lymphoblastic Leukemia, along with several other papers making new insights into the genomes of aggressive childhood cancers. But the projects used low-resolution approaches, and weren’t mapping every genome base.

The projects sparked a discussion among St. Jude researchers who began to talk in earnest about sequencing the genomes of pediatric cancer tumors in an effort to find new treatments.

“It was really in 2008 that we started talking, could it be done? What would it take? How much would it cost? What would the project look like?” Downing said.

About 85 percent of St. Jude’s faculty participated in an off-site retreat to study the feasibility of the project and to examine what St. Jude researchers might learn from applying new technology to the study of pediatric cancer. Most importantly, the researchers wondered if a project of this magnitude would cost St. Jude other important opportunities. After exploring every angle of the project, the research faculty and board overwhelmingly decided to support creating the Pediatric Cancer Genome Project.

Three years later, St. Jude has built a team of researchers that have carried out the largest sequencing project in pediatric cancer globally. While the project set out to map the genomes of 600 pediatric cancers and 600 non-tumor tissue samples from those same patients, they were ultimately able to map 700 pediatric cancer tumors. The team is still analyzing the last 200 of those sequences to validate the lesions and assess their clinical significance in additional pediatric cancers.

“It has been more successful than I ever could have predicted,” Downing said. “It (the project) is having an impact on the way we think about those tumors, and also helping us better identify high-risk tumors versus low-risk tumors. The project also is starting to have an impact on the treatment of some tumors.”

Using new genetic markers, St. Jude is able to identify patients with more aggressive high-risk tumors in some cancers that don’t respond to standard treatment. Downing says that means those patients need to be treated differently than patients who have markers that indicate they have a less-aggressive form of cancer.

In some cases, The Pediatric Cancer Genome Project also has been able to identify the pathway that causes the proliferation of cancerous cells. Downing says by establishing those pathways, researchers can begin to identify drugs that can inhibit those pathways, and ultimately cure children with cancer.

“It really began as a project to gain insights into the biologic lesions that are driving the cancers,” he said. “Our feeling was that we really don’t know that much about many of the cancers, and that if we could gain that fundamental information it would rapidly accelerate our ability to develop new ways of treating these patients.”

Now that the first phase of the project is complete, Downing says St. Jude doesn’t want to walk away from the expertise, the capital infrastructure and the global experts who have worked on the project the past three years. This spring, the research hospital will begin the second phase of the Pediatric Cancer Genome Project. The $30 million second phase will continue a discovery effort to further identify the mutations and tumors, and examine areas that were extremely difficult to analyze in the first phase of the project.

The Pediatric Cancer Genome Project will continue making its tools and data available to researchers around the world free of charge.

“The problem is massive, and we need everyone around the world working on it,” Downing said. “The project has brought people together to improve the cures with catastrophic childhood diseases.”

To vote for Downing’s inclusion in the final Time 100 list, go to http://time100.time.com/2013/03/28/time-100-poll/slide/dr-james-downing/. Voting ends Friday, April 12, and the final list, which is selected by the magazine’s editors, will be revealed April 18.

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