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Research Highlights - Spring 2015

Drs. Kanneganti and Gurung

Question yields strategy for tropical disease

Researchers like to ask basic questions about the world and how things in it work. Answers to those questions can advance science and protect health.

A recent example comes from the St. Jude lab of Thirumala-Devi Kanneganti, PhD, Immunology (pictured at left with Prajwal Gurung, PhD, Immunology). Scientists wanted to know more about how one branch of the disease-fighting immune system influences another in response to parasite infections. The researchers wound up discovering a possible strategy for fighting the most common form of a major tropical disease.

The disease is cutaneous leishmaniasis. It is caused by a parasite that spreads through the bite of infected sand flies. The infection causes skin sores that sometimes take years to heal. The results can lead to scarring and disability. Each year leishmaniasis kills thousands of people in some of the world’s poorest countries and sickens more than 1.3 million. In many countries, children are particularly vulnerable.

Researchers showed that blocking a protein named interleukin 18 (IL-18) protected specially bred mice from the infection. The results suggest that developing drugs that neutralize IL-18 could lead to better prevention and treatment of the disease. This research appeared in the Journal of Clinical Investigation.

Drug candidate destroys malaria in 48 hours

Malaria is a serious health threat to billions of people around the world, particularly children. The World Health Organization estimates that a child in Africa dies of malaria every minute. Although malaria can be cured, the parasites that cause it often develop drug resistance, complicating efforts to fight the disease.

Now, a fast-acting drug candidate developed by St. Jude scientists and collaborators offers new hope for beating malaria. The candidate, called (+)-SJ733, triggers the immune system to rapidly destroy red blood cells infected by the deadliest type of malaria parasite. After only 48 hours, the parasites are gone without a trace.

Clinical trials are being planned to test the safety of (+)-SJ733 in humans. “Our goal is to develop an affordable, fast-acting combination therapy that cures malaria with a single dose,” said R. Kiplin Guy, PhD, chair of St. Jude Chemical Biology and Therapeutics.

“These results indicate that SJ733, and other compounds that act in a similar fashion, are highly attractive additions to the global malaria eradication campaign, which would mean so much for the world’s children.”

The work was published in the Proceedings of the National Academy of Sciences.

Scientists zero-in on monocytes

The body’s immune system fights cancer. And cancer fights back. For years, researchers have known that tumors can harness healthy white blood cells to enhance their own growth and suppress attacks by the immune system. But it was unclear exactly which types of white blood cells help tumors.

The puzzle has been solved by researchers from St. Jude, who used a novel strategy to track the contribution of different types of white blood cells. They discovered that the immune suppression is primarily the work of cells called monocytes.

The laboratory findings mark a turning point in cancer immunology and provide the foundation for developing more effective immunotherapies, said Peter Murray, PhD, of St. Jude Infectious Diseases and Immunology.

“We have identified the monocytic cells as the important cell to target—not only in cancer, but possibly for treatment of autoimmune disorders like rheumatoid arthritis or inflammatory bowel diseases where dampening the immune response could provide relief,” he said.

The results were published in the scientific journal Immunity.

Add pituitary tests to survivor health checklist

St. Jude researchers have reported more evidence that many childhood cancer survivors need their pituitary function checked annually.

Investigators found that survivors remain at risk for pituitary hormone deficiencies decades after they underwent treatment with cranial irradiation. Researchers also found evidence that low hormone levels may diminish survivors’ health and quality of life.

 “The findings underscore the need for childhood cancer survivors to get recommended health screenings and challenge us to help survivors navigate the health care system and receive the care they need,” said Wassim Chemaitilly, MD, of St. Jude Pediatric Medicine. St. Jude is testing a pilot program to help cancer survivors at risk for hormone problems make a successful transition from pediatric to adult medical care.

The study appeared in the Journal of Clinical Oncology.

Taking aim at treatment-related hearing loss

St. Jude scientists have discovered inherited genetic variations that are associated with rapid hearing loss in young cancer patients treated with the drug cisplatin.

The drug is a mainstay of treatment for children and adults with many types of brain and other solid tumors. But in some patients, the drug causes severe hearing loss or other side effects.

Jun J. Yang, PhD, of St. Jude Pharmaceutical Sciences, and his colleagues checked the DNA of children with brain tumors for more than 1.7 million genetic variations. Variations in a gene named ACYP2 were associated with as much as a four-fold greater risk of cisplatin-related hearing loss.

The screening is among the first to survey the genetic landscape for clues to help explain why the risk of cisplatin-related hearing loss varies so widely among patients.

“This is an important first step in being able to pinpoint patients who are at higher risk of developing cisplatin toxicity and to learn how to better manage that risk,” said Clinton Stewart, PharmD, of St. Jude Pharmaceutical Sciences.

A report on the study appeared in the scientific journal Nature Genetics.

Abridged from Promise, Spring 2015

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