Research Highlights

John Schuetz, Aaron Pitre, Yao Wang — From left: John Schuetz, PhD; Aaron Pitre, PhD; and Yao Wang

Discovery could ease lung disorder in at-risk newborns

The bile and bile acid that aid digestion and ensure good nutrition can make life uncomfortable for some pregnant women. Their babies may also be at risk for dangerous breathing problems.

The trouble begins during pregnancy when the normal flow of bile acid and bile from the liver is interrupted, causing a blockage. Bile acid is a key component of bile. The blockage leads to a buildup of both in the liver and blood stream. Women with the problem have itchy skin until the baby is born. But about 30 percent of the newborns develop life-threatening respiratory distress.

The disorder is called intrahepatic cholestasis of pregnancy. It affects as many as 5 percent of pregnant women with no history of liver disease. St. Jude research has dramatically improved our understanding of the problem. The study also identified a lead on how to protect newborns.

Working in a laboratory model of the human disease, scientists found evidence that bile acid can cross the placenta and build up in fetal lungs. The results also suggest bile prevents proper assembly of a chemical that helps keep newborn lungs inflated. Investigators found that blocking the reabsorption of bile acid in the intestines during pregnancy eased that risk.

“The results suggest it may be possible to develop drugs to reduce the risk of newborn respiratory distress by reducing bile acid levels in maternal blood and preventing its reabsorption in the intestines,” said John Schuetz, PhD, Pharmaceutical Sciences vice chair. A report on this study appeared in the journal Nature Communications.

Scientists shine a light on dark proteome

Scientists at St. Jude, The Scripps Research Institute and other institutions recently announced the launch of the Human Dark Proteome Initiative. The project aims to foster research and collaboration about the proteins known as the “dark proteome.”

The dark proteome is the collection of proteins in an organism that do not adopt defined 3-D structures and thus are currently “unseen,” or “dark.” These proteins are extensively involved in diseases ranging from heart and infectious diseases to diabetes, cancer, Parkinson’s and Alzheimer’s.

“Our goal is to raise awareness about the potential societal impacts of a broad-based research infrastructure for these understudied proteins,” said St. Jude structural biologist Richard Kriwacki, PhD. “We also want to develop educational programs that will address the origins of and potential cures for devastating diseases affected by these proteins.”

Gene variations offer clues to cancer risk

A small change in a single gene suggests why childhood acute lymphoblastic leukemia (ALL) has turned up in two generations of one family. Research led by St. Jude investigators identified the change and found other young ALL patients had variations in the same gene.

The ETV6 gene plays an important role in the blood system. St. Jude researchers discovered that one copy of the gene is altered in a family in which the mother and two of three children are survivors of childhood ALL.

All three childhood cancer survivors carry the alteration, which is predicted to cause the gene to malfunction. The daughter who is cancer free has the same alteration. The father does not have cancer and does not carry the alteration.

When researchers checked an additional 4,405 children with ALL they found almost 1 percent had changes in the same gene. Research is underway to understand the magnitude of the risk associated with ETV6 variations and develop recommendations for monitoring affected children and families. The family in this study has received counseling and follow-up care through the St. Jude Hereditary Cancer Predisposition Clinic.

“The results also suggest that inherited susceptibility to pediatric ALL may be more common than currently believed,” said Jun J. Yang, PhD, of St. Jude Pharmaceutical Sciences. A report on this study appeared in the journal Lancet Oncology.

How salad dressing mirrors cell function

Have you ever noticed how oil and vinegar separate into droplets on a salad plate? St. Jude scientists have evidence that cells use the same process to stay organized and work properly.

The discovery answers a basic question of cell biology. The finding also shows a possible new way to treat devastating degenerative diseases like amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease; frontotemporal dementia; and inclusion body myopathy.

The mechanism is called liquid phase separation. It leads oil and vinegar to separate in salad dressing. St. Jude researchers found that under certain conditions the process may also prompt proteins with particular designs to condense into droplets inside cells. The droplets are likely the basis for temporary cell structures like stress granules. Many important cell functions take place in such structures.

Until now, the way stress granules form was not well understood. Neither was their connection to certain mutations in patients with ALS and related diseases.

This study provides that link. The findings have also fueled interest in developing treatments for diseases like ALS that work by blocking granule formation.

J. Paul Taylor, MD, PhD, a Howard Hughes Medical Institute investigator and chair of St. Jude Cell and Molecular Biology, and Tanja Mittag, PhD, of Structural Biology, led the research, which appeared in the journal Cell.

On the line: preventing blockages before they develop

Nearly every child undergoing cancer therapy receives a central venous catheter, or central line. This tube is inserted into one of the large veins leading to the heart. The line provides the blood products, medications and fluids that kids need to battle cancer. But central venous catheters have their own risks, such as blockages that can lead to life-threatening problems.

For reasons that are unclear, about 40 percent of patients develop central line blockages that require clot-dissolving drugs to clear the lines, or surgery to replace them.

“We know that having a blockage—even one that is successfully treated—is associated with an increased risk of infection, other complications and even death,” said Joshua Wolf, MBBS, Infectious Diseases.

If these occlusions were predictable, they might be preventable, but until now there has not been any way to determine which patients are at risk. Wolf developed a new technique to monitor the resistance in patients’ central lines by measuring the pressure required for a saline solution to flow through the line. A significant increase in catheter resistance or evidence of turbulent flow was linked to a nearly seven-fold increased risk of developing a blockage within the next few days.

Wolf’s research shows that monitoring catheter resistance may help clinicians prevent the problem by finding patients at risk and intervening early to treat the blockage before it occurs.

Results of the study were published in the journal PLoS One.

Skin cancer therapy also targets brain tumor subtype

A targeted therapy used to treat advanced skin cancer in adults is also effective against a subtype of the brain tumor medulloblastoma. As a result of recent research at St. Jude, this therapy is now included in the St. Jude clinical trial for newly diagnosed pediatric medulloblastoma patients.

The drug, called vismodegib, is designed to block a key protein in the sonic hedgehog (SHH) signaling pathway. There are four subtypes of medulloblastoma, each with different genetic alterations.

The SHH pathway is switched on in about 60 percent of medulloblastoma tumors in adults and 25 percent in children.

Giles Robinson, MD, Oncology, says not all children with the SHH subtype will benefit from vismodegib.

“But for the right patients, these results mark the beginning of a new era of targeted therapy,” he said. “The findings also highlight the importance of ongoing research to identify the genetic alterations that define who the right patients are and help identify those most likely to benefit from this drug, as well as those for whom different therapy is needed.”

The findings were published in the Journal of Clinical Oncology.

From Promise, Winter, 2016

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