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Highlights - Promise, Summer 2011


New test aids tailored therapy quest

St. Jude investigators have developed a new diagnostic approach that uses antibodies to assign the brain tumor medulloblastoma to different molecular subgroups based on differences in gene expression. The new test uses commercially available antibodies and works on the fixed tissue samples pathologists use in routine diagnostic practice, which should help community physicians.

David Ellison,MD, PhD, Giles Robinson, MD, and Richard Gilbertson, MD, PhD confer“The identification of molecular subgroups is not only important for understanding the origins of medulloblastoma, but has the potential for immediate clinical relevance,” said David Ellison, MD, PhD, Pathology chair. Ellison is first author of the study, which was published recently in the journal Acta Neuropathologica.

The study combined clinical, pathological and molecular factors to stratify patients as having low-, intermediate- or high-risk forms of disease, allowing a more tailored approach to therapy. Once considered a single disease, medulloblastoma is now thought to include four to six subgroups that stem from different genetic missteps. These subgroups likely respond best to different therapies and are associated with differences in outcome.

More than 500 medulloblastomas have now been subtyped using the new approach. The results come not long after an international effort led by Richard Gilbertson, MD, PhD, of Developmental Neurobiology and Oncology, showed WNT and SHH subgroup medulloblastomas arise from distinct cell types in the brain. The report also comes amid ongoing clinical trials with an experimental drug that targets the SHH pathway in adult and childhood cancers. Amar Gajjar, MD, Oncology, is principal investigator of those Pediatric Brain Tumor Consortium and other St. Jude medulloblastoma trials.

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Honored for international achievements

Raul Ribeiro, MDThe International Network for Cancer Treatment and Research recently presented Raul Ribeiro, MD, International Outreach Program director, with the Paul P. Carbone Award in International Oncology. The honor recognizes outstanding contributions to oncology or cancer research in one or more developing countries by an individual from a resource-rich country.

Since taking the helm of the International Outreach Program in 1997, Ribeiro has helped establish partnerships with 19 medical institutions in 14 countries. He is also the Leukemia/Lymphoma Division director, the St. Jude Cancer Center’s Outreach Program associate director and a member of the Oncology department.

“Dr. Ribeiro has dedicated his life to the fight against childhood cancer,” said Joseph Laver, MD, clinical director and executive vice president. “He is tireless in his mission, and his efforts have improved survival rates of children with cancer around the globe.”

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A different kind of therapy

The scrapbooking supplies were still being unpacked on a recent rainy Wednesday evening when the first parents arrived in the Ronald McDonald House dining room and got to work documenting their St. Jude story.

Paula McCarthyBefore the scrapbooking session ended two hours later, caregivers from four families had gathered around the table. Recently published St. Jude research suggests that such therapeutic scrapbooking groups increase the ability of caregivers, especially mothers, to cope with their child’s illness.

Nearly a decade after St. Jude began offering therapeutic scrapbooking as an alternative to traditional support groups, a study has found these sessions promote hopefulness, in part by helping families recognize their strengths and by expanding their support network.

“Even though the craft of scrapbooking is widespread, its use as a tool for mental health professionals is just developing,” said Social Worker Paula McCarthy (at right), lead author of the study, published in the Journal of Psychosocial Oncology. “I hope documenting our experience at St. Jude encourages others to try it in diverse settings with a variety of groups, young and old.”

McCarthy facilitates monthly scrapbooking sessions at Target House and the Ronald McDonald House. Caregivers use the scrapbooks to tell their stories and highlight both the patient’s and family’s strengths. The sessions also give McCarthy a chance to provide immediate support to parents and build connections that sometimes make it easier for caregivers to seek support later.

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Great news for hemophilia program

The St. Jude Bleeding Disorders and Hemostasis Program was recently designated as a Federal Hemophilia Treatment Center by the Maternal and Child Health Bureau. This prestigious award provides national recognition to the program and includes financial incentives that will save St. Jude approximately $1 million annually.

“The benefit of this designation is that our patients are now represented within the larger group of national patients, which means continual, high-quality standardized care,” said the program’s director, Ulrike Reiss, MD, Hematology. “The other benefit of being a hemophilia treatment center is the ability to start a drug distribution program that results in significant financial savings for St. Jude.”

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FLIP finding offers exciting potential

Work led by St. Jude scientists identified how cells flip a switch between cell survival and cell death in a process that involves a protein named FLIP.

The findings solve a riddle that has puzzled scientists for more than a decade regarding the dual nature of caspase-8, an enzyme linked to the cell’s suicide pathway but also essential for cell survival during embryonic development and in the immune response. Researchers identified FLIP and the silencing of another enzyme, named RIPK3, as playing pivotal roles. The study was published in the journal Nature.

The paper’s senior author, Douglas Green, PhD, Immunology chair, said work has begun to translate the results into potential new targets for cancer treatment and to improve understanding of the missteps that give rise to certain tumors. The work also suggests a mechanism some virus-infected cells use to subvert the immune response. “It is a rare thing to ‘cure’ a lethal mutation by removing another gene,” Green said. “When that happens, the biology shouts out to us that this is important.”

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Pediatric surgical oncology fellows visit

Andrew Davidoff, MD Andrew Davidoff, MD, Surgery chair (center), and other faculty in the St. Jude Department of Surgery hosted pediatric surgical oncology fellows from the U.S. and Canada during the Pediatric Surgical Oncology Review Course for Fellows in March. The educational conference is the only one of its kind in the nation for the surgical management of children with malignant solid tumors.

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Observing progress

Mary Pinkel with Clinton Stewart, PharmDMary Pinkel, daughter of the hospital’s founding director, Donald Pinkel, MD, recently returned to St. Jude to see the growth and progress made since her father’s tenure from 1961 to 1973. In addition to touring the lab of Clinton Stewart, PharmD, Pharmaceutical Sciences, she visited with Dr. William E. Evans, St. Jude director and CEO; Robert Webster, PhD, Infectious Diseases; and Gaston Rivera, MD, International Outreach, among other St. Jude faculty and staff.

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Cooperating mutations launch brain tumor

Mutations in three pathways important for suppressing tumors cooperate to launch glioblastoma, an aggressive brain tumor that strikes children and adults. But new research from St. Jude investigators shows those changes alone are not
sufficient to cause cancer. Tumor formation requires additional mutations, some affecting different points in the same disrupted regulatory pathways.

The laboratory findings, as well as the technique investigators used to generate them, are now being used as a possible tool for understanding patients’ responses to investigational therapies that target some of the same pathways. The research appeared in the scientific journal Cancer Cell.

The work builds on previous studies that linked glioblastoma to disruptions in the RB1, p53 and Pten pathways, each of which has a key role in preventing tumor formation. For this study, St. Jude investigators developed a novel system that allowed them to delete the genes for which the pathways are named. Researchers then tracked the impact of those deletions.

“This experimental system provides an opportunity to initiate a tumor with specific mutations and then ask, ‘What else gives the tumor a selective advantage?’” explained the paper’s senior author Suzanne Baker, PhD, Developmental Neurobiology.

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Researchers devise alternate therapy

St. Jude investigators have found an alternate chemotherapy that can be used by institutions that are unable to offer high-dose methotrexate to children with the bone cancer osteosarcoma. The alternative chemotherapy offers comparable long-term survival to the traditional therapy. The expertise and technology required for high-dose methotrexate treatment are not universally available.

The study, led by former faculty member Najat Daw, MD, also highlights a role for international collaboration in advancing clinical research. More than half of the 72 patients in this study were enrolled and treated at the St. Jude partner site in Chile. The findings appeared in the journal Cancer.

The paper’s senior author, Victor Santana, MD, Oncology, noted that the study focused on an alternative mix of chemotherapy agents—carboplatin, ifosfamide and doxorubicin.

“The results suggest the three-drug therapy may be a good alternative for institutions or countries that do not have the infrastructure to support administration of high-dose methotrexate,” Santana said.

Enrollment is currently underway for a multicenter trial that uses a new, more targeted drug called bevacizumab. The new study is led by Fariba Navid, MD, Oncology.

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Gene linked to leukemia relapse

Despite dramatically improved survival rates for childhood acute lymphoblastic leukemia (ALL), relapse remains a leading cause of death from the disease. Work led by St. Jude investigators identified mutations in a gene named CREBBP that may help the cancer resist steroid treatment and fuel ALL’s return.

Charles Mullighan, MD, PhD, and Jinghui Zhang, PhDIn this study, researchers found that 18.3 percent of relapsed ALL patients carried alterations in the DNA sequence of CREBBP. In contrast, the gene’s sequence was changed in just one of the patients whose cancer did not return.

Investigators believe the gene is a potential indicator of relapse risk because of the high frequency of CREBBP mutations in relapsed patients and evidence that the changes persisted from diagnosis or emerged at relapse from subpopulations of leukemia cells present earlier. Researchers also found evidence the changes occur in important regulatory regions of the gene and affect cell function, including how cancer cells respond to the steroids used in treatment. The work appeared in the scientific journal Nature.

“This study gives us further evidence that detailed genomic studies can identify important mutations that influence tumor response to treatment,” said Charles Mullighan, MD, PhD, Pathology. Mullighan and Jinghui Zhang, PhD, Computational Biology, are the study’s co-first authors.

Paul Brindle, PhD, Biochemistry, helped the team understand how the mutations affect cell function. “This study is an example of how basic research informs efforts to improve clinical care,” he said.

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New MRI installed

Workers install a fourth MRI scanner in the Chili’s Care Center, enhancing its state-of-the-art imaging suite and offering the most advanced high-field MRI technology available.

MRI“Imaging scientists and clinical investigators will use the new instrument to study children with pediatric cancers, sickle cell disease and HIV/AIDS, and also adult survivors of these diseases,” explained Robert Ogg, PhD, Translational Imaging Research division chief.

Imaging performance of an MRI is determined by the scanner’s magnetic field strength, which is measured in Teslas. The Chili’s Care Center previously housed one 3 Tesla and two 1.5 Tesla scanners. The new 3 Tesla MRI was funded by a grant from the National Institutes of Health, and will advance basic and clinical imaging research at St. Jude.

“St. Jude will be one of the few first sites in the United States to have the opportunity to work on this platform,” said Zoltan Patay, MD, PhD, Neuroimaging section chief. “This will keep us and our research on the cutting edge of MRI technology and allow us to grow as new advancements are made available.”

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