Cancer and Blood Diseases Institute

Significant Accomplishments

Experimental Hematology and Cancer Biology

New approach targeting NF1

Neurofibromatosis type 1 (NF1) patients develop benign neurofibromas and malignant peripheral nerve sheath tumors that remain incurable. A group led by Nancy Ratner, PhD, found that NF1 mutation causes sustained ERK activation in these tumors. They showed that an MEK inhibitor reduces aberrantly proliferating tumor cells, shrinks neurofibromas in mice, and prolongs survival of mice implanted with human cancer cells. This study, reported in the Journal of Clinical Investigation, demonstrates that deregulated ERK signaling is critical for the growth of NF1 peripheral nerve tumors and provides a strong rationale for future clinical trials.

Passing through the blood-brain barrier

Dao Pan, PhD, and colleagues discovered a non-invasive procedure to deliver large-molecule therapeutic agents across the blood-brain barrier to treat neurological disorders. Findings were published online in February 2013 in PNAS. To realize the potential of large molecular weight substances to treat neurological disorders, they fused a receptor-binding peptide from apolipoprotein E with a potentially therapeutic protein that can be transcytosed into the central nervous system in a mouse model of a lysosomal storage disorder with central nervous system defects. They demonstrated the therapeutic potential of this approach by correcting brain glycosaminoglycan and β-hexosaminidase in the mice.

Stem cell regeneration mechanism

Krüppel-like factor 5 regulates pluripotent stem cell self-renewal. In a work published in Nature Communication, Jose Cancelas Perez, MD, PhD, and colleagues reported that Krüppel-like factor 5-deficient hematopoietic stem cells and progenitors fail to engraft after transplantation. They supplied evidence that Krüppel-like factor 5 is indispensable for adhesion, homing, lodging and retention of hematopoietic stem cells and progenitors in the bone marrow through Rab5-dependent regulation of β1/β2 integrins.

Chemicals targeting G-protein coupled receptor signaling

The G-protein-mediated Rho GTPase signaling axis has been implicated in human pathophysiology and is a potential therapeutic target. Yi Zheng, PhD, and colleagues reported in PNAS, the rational design and identification of a family of small molecule inhibitors specifically targeting Rho activators to benefit cancer stem cell therapy. Their work presents a new drug design strategy for dual inhibition of an enzyme-substrate pair that leads to enhanced efficacy and specificity of a targeted therapy.

Hematology

Ware named Division Director

After a thorough search process, the Hematology Faculty and Search Committee selected Russell Ware, MD, PhD, as the new Division Director. Ware comes to Cincinnati Children’s from Baylor College of Medicine in Houston. He obtained his MD and PhD degrees from Duke University, and completed his fellowship in Pediatric Hematology/Oncology at Duke. He has been involved in clinical and translational hematology research projects for more than 25 years, with a primary interest in sickle cell disease. Ware has substantial personal experience with directing patient-oriented research, and currently runs an NIH-funded project to investigate genetic modifiers of sickle cell disease. Ware also is the national principal investigator for several NIH-funded multi-center sickle cell clinical trials, including the Stroke With Transfusions Changing to Hydroxyurea (SWiTCH), TCD With Transfusions Changing to Hydroxyurea (TWiTCH) and Sparing Conversion to Abnormal TCD Elevations (SCATE) studies. Most recently he has moved his research efforts into the international arena, starting SCD pilot screening programs in Angola, Uganda and other regions of Africa. He has published more than 225 peer-reviewed articles and has personally trained dozens of students and fellows. Ware will lead the Division of Hematology with overall goals of expanding its research portfolio, growing clinical expertise, and developing national and international prominence.

Oncology

No. 1 pediatric cancer program in the nation

The Oncology Division has had a very successful year, culminated by being named the top pediatric cancer program in the country by US News and World Report. This honor reflects successful team science, team process improvement and team clinical care initiatives that are fundamental to the Division. Key associated advances included successful bench-to-bedside implementation of faculty-led, investigator-initiated clinical trials using targeted small molecules for relapsed leukemia, brain tumors, advanced sarcomas and liver/renal tumors. These initiatives all involved close integration of translational oncology efforts between Oncology, Experimental Hematology, Blood/Marrow Transplant, Pathology, Clinical Pharmacology, and Biomedical Informatics.