$2.3 Million in New NIH Funding Extends Cancer Research Projects at Cincinnati Children’s

Thursday, April 15, 2010

CINCINNATI – Two scientific teams at Cincinnati Children’s Hospital Medical Center are receiving a total of $2.3 million in research funding from the National Institutes of Health (NIH) to continue promising studies seeking novel treatments for leukemia and bone marrow failure.

A team led by Yi Zheng, Ph.D., and James Mulloy, Ph.D., is getting a five-year grant totaling $1.04 million from NIH’s National Cancer Institute entitled, “Targeting CDC42 in Leukemia Stem Cells.” Qishen Pang, Ph.D., and colleagues are being awarded a five-year grant totaling $1.25 million from the National Heart, Lung and Blood Institute entitled, “Role of FA Protein Complexes in Hematopoiesis.”

The scientists are all part of the Cancer and Blood Diseases Institute at Cincinnati Children’s and its divisions of Experimental Hematology/Cancer Biology and Learn more about the Division of Hematology/Oncology.. Dr. Zheng is director of Experimental Hematology/Cancer Biology.

Research into CDC42 involves a protein that normally is crucial to cell adhesion, survival and migration. Scientists have learned that under certain conditions CDC42 stimulates development of disease initiating cells in bone marrow and leukemia stem cells, which they believe can fuel prolonged disease, relapse and mortality. The research team has been studying this process in Acute Myeloid Leukemia (AML), a complex blood cancer that often suffers from relapse after conventional chemotherapy treatment.

Ongoing studies of mice bred to model human leukemia – including a novel mouse model of AML developed by Dr. Mulloy’s laboratory – and of human leukemia cells have shown blocking CDC42 inhibits formation of cells that initiate leukemia and promotes programmed cell death of leukemia cells. The goal of the newly funded research is to develop a new therapeutic strategy for targeting CDC42 to eliminate leukemia stem cells in bone marrow for leukemias that are resistant to conventional chemotherapies.

Dr. Pang’s team is studying molecular mechanics of how Fanconi anemia (FA) proteins regulate cell response to oxidative stress during hematopoiesis, the process of blood cell formation in bone marrow. This is important to understanding the progression Fanconi anemia, bone marrow failure, myelodisplastic syndrome (once called pre-leukemia), AML and the underlying genomic instability in people with Fanconi anemia.

The researchers have already shown that bone marrow cells from patients with Fanconi anemia accumulate high levels of molecules called reactive oxygen species (ROS). ROS molecules are the source of oxidative stress and bone marrow cells in people with Fanconi anemia are sensitive to ROS suppressing the formation of blood stem and progenitor cells. The scientists have also demonstrated that abnormal accumulation of ROS leads to formation of leukemic cells in a mouse model of Fanconi anemia. The team has reported that a specific FA protein, FANCD2, binds and works with the transcription factor FOXO3a, which helps control the transfer of genetic information in cellular stress response processes. Together hey form a complex that helps provide a cellular defense system against oxidative stress.

By using cells from children with Fanconi anemia and working with mouse models in their continued research, the scientists hope to find new therapeutic targets to treat or prevent bone marrow failure and related cancer progression.

About Cincinnati Children’s

Cincinnati Children’s Hospital Medical Center is one of 10 children’s hospitals named to the Honor Roll in U.S. News and World Report’s 2009-10 America’s Best Children’s Hospitals. It is ranked #1 for digestive disorders and highly ranked for its expertise in respiratory diseases, cancer, neonatal care, heart care, neurosurgery, diabetes, orthopedics, kidney disorders and urology. Cincinnati Children’s is one of the top two recipients of pediatric research grants from the National Institutes of Health (NIH). Internationally recognized for quality and innovation by The Joint Commission, the Institute for Healthcare Improvement and the federal Agency for Healthcare Research and Quality, it has collaborations with hospitals and health systems around the world. Additional information can be found at www.cincinnatichildrens.org.