Children's National researchers receive NIH grant for pediatric acute myelogenous leukemia treatment

A $1.92 million grant from the National Institutes of Health (NIH) was awarded to a research team that focuses on new approaches for treatment of relapsed pediatric acute myelogenous leukemia (rAML), led by Yang Liu, PhD, Bothworth Chair and Director of the Center for Cancer and Immunology Research (CCIR) at Children's Research Institute of Children's National Health System, and Reuven Schore, MD, member of CCIR and attending physician in the Leukemia & Lymphoma Program of the Division of Oncology of the Center for Cancer and Blood Disorders.

This grant supports collaborative research between non-NIH and NIH investigators by leveraging the resources of the Clinical Research Center at the NIH. The Children's National project is among 10 across the country in which the NIH is using an innovative funding mechanism, known as U01 for cooperative agreements, for the first time.

The team is examining novel approaches to address unmet medical needs of rAML patients, among whom inducing remission is particularly difficult, and the risk of relapse is high. Dr. Liu said that therapeutic elimination of leukemia stem cells (LSC) may offer new approaches for rAML, in part, because one difficulty is that LSC are highly resistant to conventional chemotherapy and may be responsible for relapse.

"AML is a type of leukemia, affecting both children and adults, that impacts the blood and bone marrow. Although current therapies can result in complete remission in almost 90 percent of pediatric AML patients, almost 50 percent will relapse, most within two years of attaining remission," said Dr. Schore, also Assistant Professor of Pediatrics at the George Washington University School of Medicine and Health Sciences.

In their previous studies, Liu and his collaborators have shown that echinomycin, an hypoxia-inducible factor(HIF) 1 inhibitor, a class of medication, is effective in eliminating AML stem cells in xenogeneic mouse models and provides effective therapy in mouse studies of AML.

"There are questions as to why relapse occurs and whether different populations of cells can give rise to leukemia," said Liu. "Some cells resist chemotherapy and survive. In the treatment of leukemia, there have been attempts to get rid of these stem cells, but no effective way has been demonstrated to get rid of the stem cells."

Echinomycin has been used in phase I and phase II clinical trials in adult patients with solid tumors, although the drug has not been tested in hematological malignancies such as leukemia, and not yet approved by the Food and Drug Administration, Liu said. "We have shown that the drug can be very effective in AML, even with doses much lower than those used in adults in previous clinical trials, " he said.

In 2011, the researchers reported in the prestigious journal Cell Stem Cell that "HIF is activated in and essential for maintenance of AML stem cells."

The collaborative environment between clinical investigator and bench researchers at Children's National is essential for the success of the application, said Liu and Schore. "We are particularly grateful for the leadership of Dr. Jeff Dome, Chief of Divisions of Hematology and Oncology, who helped to initiate the collaboration with scientists at NIH and advised on research strategy," they added.

Dr. Liu and Dr. Schore lead the Children's National team, which includes Yin Wang, PhD, Joseph Devaney, PhD, Pamela Hinds, PhD, RN, FAAN, and Jichuan Wang, PhD, at the Children's Research Institute.

"Our proposed studies will provide the much needed first in human data on Pharmacokinetics (PK) and Pharmacodynamics of Echinomycin and provides a foundation for future phase II and Phase III clinical trials aimed at the therapeutic elimination of cancer stem cells for pediatric AML," the researchers said.

Brigitte Widemann, MD, Senior Investigator and Attending Physician at the National Cancer Institute Pediatric Branch, leads the Cancer Institute team that includes Terry Fry, MD, and Kathy Warren, MD, at the NIH.

The NIH's Clinical Center awards support projects on a variety of diseases and health conditions that affect children and adults in the U.S. and worldwide. The three-year awards of up to $500,000 a year enable scientists throughout the U.S. to collaborate using the NIH Clinical Center, in Bethesda, MD, the largest medical center in the nation devoted entirely to clinical research.

Although government scientists who work for NIH often collaborate with scientists outside of NIH, the new grants will provide these outside scientists with direct access to wide-ranging resources within the NIH Clinical Center.

Provided by Children's National Medical Center