Research Highlights - Promise Autumn 2013


Research Highlights
 

Endowment supports Evans’ work, honors past director
ALSAC and the St. Jude Boards of Directors and Governors have earmarked $5.5 million for creation of the Donald Pinkel Endowed Chair of Pediatric Cancer Treatment.

Kill the cancer, spare the heart
To resist death, cancer cells may produce high levels of suicide-inhibiting proteins, such as one called MCL1.

Cranial irradiation linked to memory issues
Cranial irradiation for treatment of childhood acute lymphoblastic leukemia (ALL) increases the risk for memory problems in adult survivors in their mid-30s.

Lung nodules: Benign, or cancer?
When a child has been diagnosed with one cancer, the last thing a parent wants to hear is, “We see a spot on your child’s lung.” Is it benign? Or has the cancer spread?

Scientists uncover secrets of T cells
St. Jude researchers have rewritten what scientists previously understood about how key immune cells are regulated.

How does leukemia develop?
Genetic mutations are recognized players in the development of acute lymphoblastic leukemia (ALL).

Ridin’ high
Like tumbleweeds blowing in the breeze, siblings “headed west” recently to enjoy Sibling Star Day activities.

Shedding light on the dark side of mitochondria
Like microscopic power plants, mitochondria produce the energy that fuels cells.

Unraveling inflammatory disorders
For decades, abnormal changes in a protein called SHP-1 have been known to underlie a variety of inflammatory and autoimmune disorders.

Genes linked to attention problems
Chemotherapy has saved the lives of many children with acute lymphoblastic leukemia (ALL), but it can increase their risk for later neurocognitive problems.


Endowment supports Evans’ work, honors past director

Dr. William E. Evans

ALSAC and the St. Jude Boards of Directors and Governors have earmarked $5.5 million for creation of the Donald Pinkel Endowed Chair of Pediatric Cancer Treatment. The endowment, among the largest of its kind in the country, honors the hospital’s first director and will be held by the sitting St. Jude CEO. Dr. William E. Evans, the present St. Jude director and CEO, is its first designee. The endowment provides support for the CEO’s research and academic programs.

“I am deeply honored to be named the first Donald Pinkel Endowed Chair,” Evans said. “When I first came to St. Jude in 1972 as a student, Dr. Pinkel was the director, and he was a person whom everyone looked up to, largely because he did not expect more out of others than he expected from himself. He led by example. I respected him because of what he had already accomplished, and because he was interested in hearing everyone’s ideas, even those of a student like me.”

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Kill the cancer, spare the heart

Cancer cells are notoriously good at evading death by blocking cell suicide pathways, which normally eliminate damaged, dangerous or unneeded cells. To resist death, cancer cells may produce high levels of suicide-inhibiting proteins, such as one called MCL1.

So, why not create drugs that prevent MCL1 from working, and let the cancer cells kill themselves? St. Jude scientists have found it may not be so simple, because MCL1 is also essential for normal cardiac function. The researchers, reporting in Genes and Development, observed rapid and devastating consequences when MCL1 was eliminated in heart muscle.

“These findings suggest that cancer-related drug development efforts should focus on reducing MCL1 expression in target cells rather than eliminating the protein’s function completely,” said Joseph Opferman, PhD, of St. Jude Biochemistry.

The new results also suggest that providing higher levels of MCL1 in heart muscle cells might benefit a patient recovering from heart damage.

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Cranial irradiation linked to memory issues

Cranial irradiation for treatment of childhood acute lymphoblastic leukemia (ALL) increases the risk for memory problems in adult survivors in their mid-30s, according to a St. Jude study published in Journal of the National Cancer Institute.

Several years ago, St. Jude eliminated cranial irradiation from leukemia treatment after demonstrating cure rates were not compromised. But many of the estimated 50,000 pediatric ALL survivors nationwide were treated with brain irradiation. According to Greg Armstrong, MD, of St. Jude Epidemiology and Cancer Control, these survivors may benefit from continued screening for changes in memory and cognitive functioning.

St. Jude researchers are working to find interventions, said Kevin Krull, PhD, of Epidemiology and Cancer Control. In the meantime, keeping mentally, physically and socially active may help delay progression of symptoms, he said.

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Lung nodules: Benign, or cancer?

When a child has been diagnosed with one cancer, the last thing a parent wants to hear is, “We see a spot on your child’s lung.” Is it benign? Or has the cancer spread?

Answering this question is critical. Twenty years ago, patients with lung nodules faced invasive diagnostic surgery that could delay cancer treatment for weeks. Since then an alternative approach, combining CT scans, interventional radiology and minimally invasive surgery, has been widely used to diagnose and remove lung nodules, but there have been few reports about how children fared under this approach.

Now, new findings from St. Jude have demonstrated that the minimally invasive procedure is safe and effective in children. The research was published recently in the Journal of Pediatric Surgery. Senior author Bhaskar Rao, MD, of St. Jude Surgery, noted, “This technique helps to reduce the physical and psychological burden on young patients and their families.”

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Scientists uncover secrets of T cells

St. Jude researchers have rewritten what scientists previously understood about how key immune cells are regulated. The recent work focused on white blood cells known as regulatory T cells. These cells help to protect healthy tissue from misguided immune attacks or to prevent runaway inflammation.

Hongbo Chi, PhD, and Hu Zeng, PhD

St. Jude researchers showed that a molecular complex called mTORC1 uses an unconventional process to control the supply and function of regulatory T cells.

“These results challenge the prior view of the mTOR pathway as an inhibitor of these key immune cells and highlight the role of the mTORC1 complex in regulating the T cells that are vital for controlling inflammation,” said Hongbo Chi, PhD (at right), of St. Jude Immunology. Chi, postdoctoral fellow Hu Zeng, PhD (at left), and their colleagues published their findings in the journal Nature.

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How does leukemia develop?

Genetic mutations are recognized players in the development of acute lymphoblastic leukemia (ALL). But recent research points to another possible culprit underlying ALL: epigenetic changes, which are modifications to DNA that can instruct genes to turn on or off.

The researchers focused on an epigenetic process called cytosine methylation, which modifies a building block of DNA. Each subtype of ALL they examined displayed a unique methylation pattern that correlated with gene expression.

“It is well known that different leukemia subgroups have distinct patterns of gene expression that are important in the development of leukemia,” said Charles Mullighan, MBBS (Hons), MSc, MD, of St. Jude Pathology.

“We have assumed that the underlying genetic changes are important determinants of those gene expression profiles. We now know that changes in methylation state also have key roles in influencing gene expression,” he added.

The study was reported in the Journal of Clinical Investigation.

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Sibling Star Day

Ridin’ high


Like tumbleweeds blowing in the breeze, siblings “headed west” recently to enjoy Sibling Star Day activities. Employees and volunteers lined the red carpet and cheered the young cowboys and cowgirls as they arrived for a special day hosted by the Child Life Program.

This year’s event featured Western-themed arts-and-crafts activities and a luncheon to show appreciation for the contributions that siblings make as part of the patient care team.


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Shedding light on the dark side of mitochondria

Like microscopic power plants, mitochondria produce the energy that fuels cells. However, they also have a dark side: buildup of defective mitochondria inside cells can lead to neurodegenerative disorders such as Parkinson’s disease and amyotrophic lateral sclerosis.

Research from St. Jude has now shed light on the molecular underpinnings of this problem. Scientists discovered that disease-causing mutations in a gene called VCP lead to accumulation of defective mitochondria inside muscle and nerve cells. The researchers demonstrated that VCP works with two other proteins, also implicated in neurodegenerative disease, in a quality control process that recognizes damaged mitochondria and leads to their disposal.

The findings, published recently in Neuron, raise the possibility that disorders associated with VCP mutations could be treated with small molecules now under development, observed J. Paul Taylor, MD, PhD, of Developmental Neurobiology. “We have begun screening compounds,” he said.

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Unraveling inflammatory disorders

For decades, abnormal changes in a protein called SHP-1 have been known to underlie a variety of inflammatory and autoimmune disorders. But only recently did St. Jude scientists figure out how this happens—and develop leads on how to prevent it.

The researchers, publishing in Nature, teased apart the details of a complex web of interactions between SHP-1 and other molecules important for fueling inflammation. Scientists found that an inflammatory disorder caused by abnormal SHP-1 could be completely prevented by blocking a single molecule, IL-1 alpha. They also discovered the experimental drug necrostatin 1 protected against inflammation-driven tissue damage caused by abnormal SHP-1.

The findings hold clues for designing the next generation of anti-inflammatory drugs that work more selectively and do not leave patients at risk for infectious diseases and other problems. “These results are a stepping stone that leads to the clinic,” observed Thirumala-Devi Kanneganti, PhD, of St. Jude Immunology.

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Genes linked to attention problems

Chemotherapy has saved the lives of many children with acute lymphoblastic leukemia (ALL), but it can increase their risk for later neurocognitive problems. New St. Jude research published in the Journal of Clinical Oncology points to specific genetic variations that influence this risk.

About 40 percent of survivors in the study had problems with attention or processing information. Problems were more likely to occur in survivors with particular variations in any of four genes.

St. Jude researchers are working on interventions to protect neurocognitive skills in young cancer survivors. In addition, said Kevin Krull, PhD, of St. Jude Epidemiology and Cancer Control, families can help enhance their children’s neurocognitive development by encouraging children to stay physically and cognitively active and to eat a healthy diet.

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Abridged from Promise, Autumn 2013


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