First studies in Pediatric Cancer Genome Project identify genetic changes in leukemia, retinoblastoma

Early results of an unprecedented, three-year effort to fully sequence 600 pediatric cancer genomes by 2013 has provided new insights into the pathology of two different cancers—and importantly, new potential treatment targets

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MEMPHIS, Tenn.—Researchers at St. Jude Children's Hospitalhave published the first of many studies expected to be released this year thatare part of the Pediatric Cancer Genome Project (PCGP), a joint project with WashingtonUniversity School of Medicine in St. Louis that aims to identify the geneticchanges associated with some of the deadliest forms of childhood cancer.
This unprecedented, three-year effort, launched in January2010, seeks to fully sequence 600 pediatric cancer genomes by 2013. With someof this work having been completed, two studies reported in the Jan. 11 advanceonline edition of Nature provide newinsights into the pathology of two different cancers—and importantly, newpotential treatment targets.
In one study, researchers show that early T-cell precursorALL (ETP-ALL), a subtype of acute lymphoblastic leukemia (ALL) that ischaracterized by a poor prognosis, is fueled by mutations in pathways that aredistinctly different from acute myeloid leukemia (AML), a leukemia associatedwith a much better outcome. These results suggest ETP-ALL has more in commonwith AML than with other subtypes of ALL, the most common childhood cancer.
According to St. Jude's, many ETP-ALL patients fail torespond to current therapy and never enter remission. Only 30 to 40 percent ofthese patients become long-term survivors, compared to about 80 percent ofchildren battling other T-ALL subtypes. ETP-ALL was selected for inclusion inthe PCGP due to these poor outcomes and the lack of information on the geneticlesions that underlie this aggressive subtype of leukemia.
Dr. Charles Mullighan, an associate member of the St. JudeDepartment of Pathology and one of the study's corresponding authors, says themutations and gene expression profile identified in the study suggest thatpatients with ETP-ALL might benefit from treatment that includes drugsdeveloped for treatment of AML. Mullighan and his colleagues are now working todevelop laboratory models of human ETP-ALL to help identify AML drugs that aremost likely to benefit ETP-ALL patients. The list of possible drugs includeshigh-dose cytarabine and targeted chemotherapy agents that inhibit activity inthe cytokine receptor, as well as JAK signaling pathways found in this study tobe disrupted in ETP-ALL patients.
"Our overarching hypothesis was that if we want to developmore targeted therapies, then we need to identify more rational targets. Theremay be pathways that are therapeutically targetable, but clearly, we know thatleukemia is driven by genetic changes. At one level, we were hoping we mightget some low-hanging fruit and find some other therapeutic targets that may beactivating on-the-shelf materials that can be used to drug those targets. Butour broader, long-term goal is to make very fundamental insights about leukemiaepigenetics, and have some clear approaches emerge from that."
In a second study, researchers have provided a betterunderstanding of the development of retinoblastoma (RB), a rare childhood tumorof the retina, the light-sensing tissue at the back of the eye. These tumorstend to develop rapidly, while other cancers can take years or even decades toform.
According to the PCGP, more than 5,000 children worldwidedevelop RB each year, including about 300 in the United States. Most are fiveyears old or younger—and some are infants when the cancer is discovered, makingthem among the youngest cancer patients. While 95 percent of patients are curedwith current therapies if their tumors are discovered before they spread beyondthe eye, the prognosis is much worse for children in developing countries whosecancer is often advanced when it is discovered.
Previously, researchers knew that loss of the tumorsuppressor gene RB1 launches RB during fetal development, but the other stepsinvolved in the rapid transformation from a normal cell to a malignant tumorcell that occurs in this cancer were unknown. The new study explains why thetumor develops so rapidly, while othercancers can take years or even decades to form.
This study linked the RB1 mutation to abnormal activity ofother genes linked to cancer without changing the makeup of the genesthemselves. Evidence suggested that epigenetic factors, including reversiblechemical changes that influence how genes are switched on and off in tumorcells, are altered when RB1 is mutated.
Dr. Michael Dyer, a member of the St. Jude Department ofDevelopmental Neurobiology and one of the study's corresponding authors, saysthe findings could result in a new treatment target and possible therapy forRB.
"To our surprise and excitement, what we found was thatinstead of cancer genes having genetic mutations, they were beingepigenetically regulated differently than normal cells," Dyer says.
The genes included SYK, which is required for normal blooddevelopment and has been linked to other cancers. Drugs targeting the SYKprotein are already in clinical trials for adults with leukemia and rheumatoidarthritis, but SYK has no role in normal eye development. When researchers usedthe experimental drugs to block SYK in human RB cells growing in the laboratoryor in the eye of a mouse, the cells died. Dyer and his colleagues are nowworking to reformulate one of the experimental drugs, a SYK-inhibitor calledR406, so it can be delivered directly into the eye. If successful, thoseefforts are expected to lead to a Phase I trial in RB patients.
Both scientists share that the research community can expecta wealth of data to be released this year related to a variety of otherpediatric cancers as the PCGP moves forward.
"I think this project is a testament to how quickly thingscan move if you have the right players in place," says Dyer. "We have acomprehensive translational research team of medicinal chemists,pharmacologists, physicians, clinicians and basic scientists, and having thatkind of team in place allows you to move very quickly."
Data from both studies are available at no cost toinvestigators on the PCGP Explore website, which can be accessed at

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