Highlights - Promise Summer 2012


Research Highlights

 


Dr. William E. Evans; Ching-Hon Pui, MD; Brenda Schulman, PhD; Guillermo Oliver, PhD Faculty members honored

Four St. Jude faculty members have recently won national and international honors for their achievements.

In March of 2012, Dr. William E. Evans, director and CEO, received the pharmacy profession’s highest recognition, the Remington Honor Medal. Presented by the American Pharmacists Association, the award honors Evans for his research with anticancer agents and pharmacogenomics, as well as his leadership contributions to St. Jude.

The American Society of Clinical Oncology presented the 2012 Pediatric Oncology Award to Ching-Hon Pui, MD, Oncology chair. The honor recognizes Pui’s many contributions to better understanding the biology and treatment of leukemia, as well as his role in improving survival rates for the disease.

Brenda Schulman, PhD, of Structural Biology was named to the 2012 class of new Fellows and Foreign Honorary Members of the American Academy of Arts and Sciences. Schulman was elected for her contributions to understanding a major form of cellular regulation. Studies by Schulman’s laboratory have helped explain the structure and function of a family of enzymes known as ubiquitin-like proteins, which help regulate cell division.

Guillermo Oliver, PhD, of Genetics was elected a fellow in the American Association for the Advancement of Science. Oliver was chosen for his contributions to the field of developmental biology and the lymphatic vascular system.

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Inherit the risk

St. Jude scientists have pinpointed genetic factors that increase Hispanic children’s risk of having acute lymphoblastic leukemia (ALL) and of dying from the disease.

Researchers studying a gene called ARID5B linked a number of common variants of the gene to an increased risk of developing pediatric ALL and having the cancer return after treatment. Investigators found that Hispanic children were up to twice as likely as their white counterparts to inherit a high risk-version of ARID5B.

“For years we have known about ethnic and racial disparities in ALL risk and outcome, but the biology behind it has been elusive. Therefore, it is truly exciting to be able to not only pin down the biological basis but to find that the same gene might be responsible for both differences,” said Jun Yang, PhD, of Pharmaceutical Sciences. Yang was corresponding author of a report on this study, which appeared in the Journal of Clinical Oncology.

The findings set the stage for exciting research in understanding how genetic, environmental and other factors combine in ALL, especially in the context of racial and ethnic disparity. Yang said additional work is needed to translate these findings into new clinical tools.

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How sulfa drugs kill bacteria

More than 70 years after the first sulfa drugs helped to revolutionize medical care and save millions of lives, St. Jude scientists have determined at an atomic level the mechanism these medications use to kill bacteria. The discovery provides the basis for a new generation of antibiotics that would likely be harder for bacteria to resist and cause fewer side effects.

The work focused on sulfa drugs and their target enzyme, dihydropteroate synthase (DHPS).

“The structure we found was totally unexpected and really opens the door for us and others to design a new class of inhibitors targeting DHPS that will help us avoid side effects and other problems associated with sulfa drugs,” said Stephen White, DPhil, Structural Biology chair. White was corresponding author of a paper on this study that appeared in the journal Science.

Co-author Richard Lee, PhD, of Chemical Biology and Therapeutics, added: “Now we want to leverage this information to develop drugs against the opportunistic infections that threaten so many St. Jude patients.”

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When chemotherapy is best

An international study found that bone marrow transplants are not the best option for some young patients with acute lymphoblastic leukemia (ALL) whose disease does not go into remission after the initial weeks of intense chemotherapy known as induction therapy.

The largest study ever of such patients identified a subset of young children who achieved 10-year survival rates of 72 percent after additional chemotherapy rather than bone marrow transplantation. The patients are among the estimated 85 percent of children with ALL whose cancer begins in white blood cells destined to become B cells. These patients were 1 to 6 years old at diagnosis and had favorable leukemic cell genetic abnormality. This subset represented about 25 percent of the patients for whom initial remission induction had failed.

Results of the study, which involved more than 44,000 patients from the U.S., Europe and Asia, appeared in the New England Journal of Medicine.

“Induction failure is a rare event, affecting just 2 to 3 percent of all pediatric ALL patients,” said the study’s corresponding author, Ching-Hon Pui, MD, Oncology chair. “But these children are at very high risk for a bad outcome and were always considered candidates for bone marrow transplantation. These results tell us that induction failure should no longer be considered an automatic indication for a transplant.”

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Fostering tomorrow’s scientists

Forty-three top graduate students representing 34 universities across the United States delivered oral and poster presentations as part of the 11th annual St. Jude National Graduate Student Symposium. The invitation-only conference brings students representing diverse scientific backgrounds to St. Jude to present their research, learn about the institution and interact with the hospital’s scientific community. University of California, San Francisco, graduate student Justin Chen describes his research to (from left) Jian Zuo, PhD, of Developmental Neurobiology and Tal Teitz, PhD, of Tumor Cell Biology.

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A protein’s surprising functions

St. Jude scientists have rewritten the job description of a protein called TopBP1 after demonstrating that it guards early brain cells from DNA damage. Such damage might foreshadow later problems, including cancer.

Researchers showed that cells in the developing brain require TopBP1 to prevent DNA strands from breaking as the molecule is copied before cell division. Investigators also discovered that stem cells and immature cells known as progenitor cells involved at the beginning of brain development are more sensitive to unrepaired DNA damage than progenitor cells later in the process. Although more developmentally advanced than stem cells, progenitor cells retain the ability to become one of a variety of more specialized neurons.

“Such DNA strand breaks have great potential for creating mutations that push a normal cell toward malignancy,” said Peter McKinnon, PhD, of Genetics. McKinnon is senior author of a report on this research that appeared in the scientific journal Nature Neuroscience. Results of this study offer new insights into normal brain development, DNA damage repair mechanisms and cancer biology.

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Story of lymphatic system expands

A century after the valves that link the lymphatic and blood systems were first described, St. Jude scientists have detailed how those valves form and identified a gene that is critical to the process.

The gene is Prox1. Earlier work led by Guillermo Oliver, PhD, of Genetics, showed Prox1 was essential for formation and maintenance of the entire lymphatic vasculature. A network of vessels and ducts, the lymphatic vasculature helps maintain the body’s fluid balance and serves as a highway along which everything from cancer cells to disease-fighting immune components moves. Oliver is senior author of the new study, which appeared in the scientific journal Genes & Development.

The new research suggests that Prox1 is also essential for proper formation of the one-way valves that control movement of fluid and nutrients from the lymphatic system into the blood stream. Researchers found evidence that the Prox1 protein also has a critical role in formation of the venous valves.

“Understanding how valves form is crucial to efforts to develop treatments for valve defects that affect both children and adults,” said the paper’s first author, R. Sathish Srinivasan, PhD, of Genetics. Those defects are linked to a variety of problems, including lymphedema and deep vein thrombosis.

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Danny Thomas/ALSAC PavlionDanny Thomas/ALSAC Pavilion renovated


In conjunction with the hospital’s 50th anniversary celebration, the Danny Thomas/ALSAC Pavilion recently underwent renovations, adding new exhibits to spotlight the rich history and accomplishments of Danny Thomas, St. Jude and ALSAC. The facility is open Sunday through Friday, 8 a.m. to 4 p.m., and Saturday, 10 a.m. to 4 p.m. Admission is free.

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Good FORTUNE

St. Jude has been recognized by FORTUNE magazine as one of the “100 Best Companies to Work For” for the second consecutive year. Employees again ranked pride in the hospital’s mission—finding cures, saving children—as one of the top reasons St. Jude is a great place to work.

“Our employees look at the work they do at St. Jude as much more than a job,” said Dr. William E. Evans, director and CEO. “As we celebrate our 50th anniversary this year, we are reminded that one of the keys to our success has been attracting outstanding people and giving them a place to do their best work. Employees embrace the mission and espouse the culture of St. Jude, which is one of collaboration, compassion, innovation and quality in all we do.”

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A event to remember

Patients and siblings recently had the opportunity to dress up and celebrate during the hospital’s 2012 Teen Formal. Prior to their journey down the red carpet, the partygoers prepared for the big night. Girls had their hair, make-up and nails done while the boys donned sharp-looking tuxedoes before boarding limousine buses bound for the hospital. Events such as the Teen Formal, organized by Child Life staff, provide a fun respite for teen patients who might otherwise miss this rite of passage while undergoing treatment. Navigating the red carpet while acknowledging the applause of families and staff are Morgan Harris (seated) and her sister, Breanna.

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The importance of form and function

Scientists have discovered that a protein vital for cell survival and immune balance also has another form with a different function. This finding could yield an additional cancer treatment strategy.

Safeguarding cell survival and maintaining a balanced immune system are only two tasks of the myeloid cell leukemia sequence 1 (MCL1) protein. Nearly 20 years after MCL1 was discovered, scientists have identified a second form of the protein that works in a different location in cells and performs a different function. This newly identified version is shorter and toils inside rather than outside mitochondria where it assists in production of chemical energy that powers cells. The research appears in the journal Nature Cell Biology. Investigators say that the finding will likely aid the development of cancer drugs.

“We believe this newly identified form of MCL1 that works inside the mitochondria is probably essential for tumor cell survival. If that proves to be correct, then strategies to block the protein from getting into mitochondria offer a new therapeutic approach for cancer treatment,” said the paper’s senior author, Joseph Opferman, PhD, of Biochemistry.

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Equal access helps close the gap

A new analysis from St. Jude adds to evidence that equal access to comprehensive treatment and supportive care typically translates into equally good outcomes for most young African-American and white cancer patients.

Racial disparities in cancer survival are widely recognized among African-American patients of any age. These patients are less likely than their white counterparts to become long-term cancer survivors. However, researchers found no significant difference in survival rates between African-American and white children treated at St. Jude for virtually all cancers during a 15-year period ending in 2007.

While this and previous studies have highlighted the success of St. Jude in closing the gap, investigators reported that the disparities persisted for many other U.S. pediatric cancer patients.

“This study shows that with outstanding medical care and psychosocial support African-American patients should not necessarily fare worse than white patients,” said Oncology Chair Ching-Hon Pui, MD, lead author of a report on this study that appeared in the Journal of Clinical Oncology.

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Reprinted from Promise Summer 2012

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