First studies in Pediatric Cancer Genome Project identify genetic changes in leukemia, retinoblastoma
by Amy Swinderman  |  Email the author


MEMPHIS, Tenn.—Researchers at St. Jude Children's Hospital have published the first of many studies expected to be released this year that are part of the Pediatric Cancer Genome Project (PCGP), a joint project with Washington University School of Medicine in St. Louis that aims to identify the genetic changes associated with some of the deadliest forms of childhood cancer.  
This unprecedented, three-year effort, launched in January 2010, seeks to fully sequence 600 pediatric cancer genomes by 2013. With some of this work having been completed, two studies reported in the Jan. 11 advance online edition of Nature provide new insights into the pathology of two different cancers—and importantly, new potential treatment targets.  
In one study, researchers show that early T-cell precursor ALL (ETP-ALL), a subtype of acute lymphoblastic leukemia (ALL) that is characterized by a poor prognosis, is fueled by mutations in pathways that are distinctly different from acute myeloid leukemia (AML), a leukemia associated with a much better outcome. These results suggest ETP-ALL has more in common with AML than with other subtypes of ALL, the most common childhood cancer.  
According to St. Jude's, many ETP-ALL patients fail to respond to current therapy and never enter remission. Only 30 to 40 percent of these patients become long-term survivors, compared to about 80 percent of children battling other T-ALL subtypes. ETP-ALL was selected for inclusion in the PCGP due to these poor outcomes and the lack of information on the genetic lesions that underlie this aggressive subtype of leukemia.  
Dr. Charles Mullighan, an associate member of the St. Jude Department of Pathology and one of the study's corresponding authors, says the mutations and gene expression profile identified in the study suggest that patients with ETP-ALL might benefit from treatment that includes drugs developed for treatment of AML. Mullighan and his colleagues are now working to develop laboratory models of human ETP-ALL to help identify AML drugs that are most likely to benefit ETP-ALL patients. The list of possible drugs includes high-dose cytarabine and targeted chemotherapy agents that inhibit activity in the cytokine receptor, as well as JAK signaling pathways found in this study to be disrupted in ETP-ALL patients.  
"Our overarching hypothesis was that if we want to develop more targeted therapies, then we need to identify more rational targets. There may be pathways that are therapeutically targetable, but clearly, we know that leukemia is driven by genetic changes. At one level, we were hoping we might get some low-hanging fruit and find some other therapeutic targets that may be activating on-the-shelf materials that can be used to drug those targets. But our broader, long-term goal is to make very fundamental insights about leukemia epigenetics, and have some clear approaches emerge from that."
In a second study, researchers have provided a better understanding of the development of retinoblastoma (RB), a rare childhood tumor of the retina, the light-sensing tissue at the back of the eye. These tumors tend to develop rapidly, while other cancers can take years or even decades to form.  
According to the PCGP, more than 5,000 children worldwide develop RB each year, including about 300 in the United States. Most are five years old or younger—and some are infants when the cancer is discovered, making them among the youngest cancer patients. While 95 percent of patients are cured with current therapies if their tumors are discovered before they spread beyond the eye, the prognosis is much worse for children in developing countries whose cancer is often advanced when it is discovered.  
Previously, researchers knew that loss of the tumor suppressor gene RB1 launches RB during fetal development, but the other steps involved in the rapid transformation from a normal cell to a malignant tumor cell that occurs in this cancer were unknown. The new study explains why the tumor develops so rapidly, while other cancers can take years or even decades to form.  
This study linked the RB1 mutation to abnormal activity of other genes linked to cancer without changing the makeup of the genes themselves. Evidence suggested that epigenetic factors, including reversible chemical changes that influence how genes are switched on and off in tumor cells, are altered when RB1 is mutated.  
Dr. Michael Dyer, a member of the St. Jude Department of Developmental Neurobiology and one of the study's corresponding authors, says the findings could result in a new treatment target and possible therapy for RB.
"To our surprise and excitement, what we found was that instead of cancer genes having genetic mutations, they were being epigenetically regulated differently than normal cells," Dyer says.  
The genes included SYK, which is required for normal blood development and has been linked to other cancers. Drugs targeting the SYK protein are already in clinical trials for adults with leukemia and rheumatoid arthritis, but SYK has no role in normal eye development. When researchers used the experimental drugs to block SYK in human RB cells growing in the laboratory or in the eye of a mouse, the cells died. Dyer and his colleagues are now working to reformulate one of the experimental drugs, a SYK-inhibitor called R406, so it can be delivered directly into the eye. If successful, those efforts are expected to lead to a Phase I trial in RB patients.  
Both scientists share that the research community can expect a wealth of data to be released this year related to a variety of other pediatric cancers as the PCGP moves forward.  
"I think this project is a testament to how quickly things can move if you have the right players in place," says Dyer. "We have a comprehensive translational research team of medicinal chemists, pharmacologists, physicians, clinicians and basic scientists, and having that kind of team in place allows you to move very quickly."  
Data from both studies are available at no cost to investigators on the PCGP Explore website, which can be accessed at  

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