Researcher at Childrens Hospital LA discovers way to overcome radiation resistance in leukemia

Radiation-resistant leukemia cells can be killed by radiation after inhibition of a molecular target by a rationally designed new drug.

LOS ANGELES (September 29, 2010) – A team of researchers lead by Fatih M. Uckun, MD, PhD, of The Saban Research Institute of Childrens Hospital Los Angeles has determined that radiation resistance in leukemia can be overcome by selectively attacking a molecular target known as SYK tyrosine kinase.

B-lineage acute lymphoblastic leukemia (ALL) is the most common cancer occurring in children and adolescents. Despite having received intensive chemotherapy, some patients have recurring disease, known as relapse. For these individuals, the prospect of long-term survival is poor.

The standard approach to treating relapsed patients has been additional chemotherapy to achieve a second remission followed by very intensive treatment that could include "supralethal" chemotherapy, total-body irradiation (TBI), and hematopoietic stem cell transplantation. However, radiation resistance of leukemia cells hampers the success of these rigorous therapeutic approaches and results in poor survival.

Caption: This is Fatih Uckun, M.D., Ph.D., of Childrens Hospital Los Angeles. Credit: Courtesy of Dr Uckun. Usage Restrictions: None.

"We knew that we could kill radiation-resistant leukemia cells if we only knew what made them so resistant. So we set out to determine the mechanism," said Dr. Uckun, who is also professor of Research Pediatrics at the Keck School of Medicine at the University of Southern California. "Once we determined the mechanism, the next step was obvious -- to rationally design a drug that would take out that specific target."

Uckun's research team has now provided the first proof-of-principle that radiation resistance of an aggressive leukemia can indeed be overcome using this rationally-designed specific drug directed against the resistance machinery of leukemia cells.

"Radiation therapy was much more effective against leukemia in mice when it was combined with this new drug candidate that we named C-61," said Dr. Uckun. ###

The results of the study will be published in the October 2010 issue of Radiation Research, the official journal of the Radiation Research Society.

The Saban Research Institute at Childrens Hospital Los Angeles is among the largest and most productive pediatric research facilities in the United States, with 100 investigators at work on 186 laboratory studies, clinical trials and community-based research and health services. The Saban Research Institute is ranked eighth in National Institutes of Health funding among children's hospitals in the United States.

Founded in 1901, Childrens Hospital Los Angeles is one of the nation's leading children's hospitals and is acknowledged worldwide for its leadership in pediatric and adolescent health. Childrens Hospital Los Angeles is one of only seven children's hospitals in the nation – and the only children's hospital on the West Coast – ranked for two consecutive years in all 10 pediatric specialties in the U.S. News & World Report rankings and named to the magazine's "Honor Roll" of children's hospitals.

Childrens Hospital Los Angeles is a premier teaching hospital and has been affiliated with the Keck School of Medicine of the University of Southern California since 1932.

Reference: F. M. Uckun, I. Dibirdik, S. Qazi (2010) Augmentation of the Antileukemia Potency of Total-Body Irradiation (TBI) by a Novel P-site Inhibitor of Spleen Tyrosine Kinase (SYK). Radiation Research: October 2010, Vol. 174, No. 4, pp. 526-531.

Contact: Ellin Kavanagh ekavanagh@chla.usc.edu 323-361-8505 Children's Hospital Los Angeles