Past Recipients - 2007

FELLOWSHIPS

Daniel C. Link, M.D.
Ghada Kunter, M.D. (Fellow)
Washington University (St. Louis, Missouri)
Identifying the genetic progression factors of Leukemogenesis in severe congenital Neutropenia.

A rare hereditary bone marrow failure syndrome called severe congenital neutropenia (SCN) has a very high death rate - nearly 50 percent of the children born with the syndrome will die within the first year of life. Those children who do survive are left with the real threat of developing acute myeloid leukemia (AML). Their risk is a staggering 200 percent higher than the general population and it increases as the children age, reaching 36 percent by age 12. While allogenic bone marrow transplantation offers the only hope of cure for patients with AML, it is a risky procedure with high mortality and morbidity rates. The genetic mutations that contribute to the progression of SCN to AML remain unknown. Now Drs. Link and Kunter are working to identify these molecular mechanisms in hopes of developing more targeted and less harsh treatment for this subset of patients.

Dennis P.M. Hughes, M.D., Ph.D.
Pingyu Zhang, Ph.D. (Fellow)
University of Texas M.D. Anderson Cancer Center
Pharmacological and genetic blockade of HES1 in osteosarcoma suppresses invasiveness and metastasis in vitro and in vivo.

The most common type of bone malignancy in adolescents is osteosarcoma, which very often spreads to tissue beyond the bone. Ninety percent of osteosarcoma patients already have pulmonary metastasis or micrometastasis when they are diagnosed. And less than 30 percent of patients with metastatic disease survive - a statistic that hasn't improved in more than 20 years. Dr. Hughes and Zhang are investigating a promising new approach to treating metastatic osteosarcoma through a mechanism called Notch signaling. The Notch signaling network within cells is critical for normal tissue development. Previous research suggests that this network is frequently deregulated in human cancer cells, making it an appropriate target for genetic or pharmacological manipulation. In this study, researchers are working to clarify how the Notch pathway is expressed in the genes of osteosarcoma cells and identify the effects of Notch signaling on the growth, survival and invasiveness of osteosarcoma cells. This information may provide the data needed to mount a clinical trial of ?-secretase inhibitor, a drug that blocks Notch signaling, and may ultimately provide a more effective therapy—and improved outcomes—for children with osteosarcoma.

GRANTS

D. Ashley Hill, M.D.
Washington University (St. Louis, Missouri)
Genetic Characterization of the Pleuropulmonary Blastoma Family Cancer Syndrome

Pleuropulmonary Blastoma (PPB) is a rare and frequently fatal lung cancer that affects young children. For 25 to 30 children and families affected each year, the diagnosis is devastating. Most children with PPB develop their tumors in the first five years of life, and only half of these children survive. Dr. Hill is part of a team of scientists who have been studying PPB for the past 20 years—research that helped to identify risk for PPB in some families and clarified the tumor's origins during organ development. PBB also seems to be related to other childhood tumors including rhabdomyosarcoma and Wilms tumor. Still, the molecular mechanism of PPB and how it passes in genes from one generation to the next is still unknown. In this study, Dr. Hill is working to identify the genes and molecular pathways associated with PPB—information that could lead to improved diagnostic tools, genetic screening tests and better therapeutic options.

Chitra Subramanian, Ph.D.
University of Michigan (Ann Arbor, Michigan)
A novel acetylation sensitive anti-tumor mechanism in pediatric solid tumors

Solid tumors are the most difficult to treat in children. But recent research is pointing toward a more effective therapeutic approach. Dr. Subramanian has identified a novel treatment approach using HDACIs—histone deacetylases inhibitors. Because changes in histone deacetylase enzymes are common abnormalities in many cancer cells, including solid tumors, inhibiting their action could prove to be an effective treatment. But it isn't clear how histone deacetylase inhibitors work within cells. Recently, Dr. Subramanian identified a novel mechanism for HDACIs in neuroblastoma (NB), the most common pediatric solid tumor. In this current study, the research team continues to define how HDACIs work and to determine which histone deacetylase enzymes are most important to the development of tumors. This information may be used in the design of more effected targeted therapy for solid tumors.

Julien Sage, M.D.
Stanford University
Modeling Retinoblastoma

Despite advances in treatment of pediatric tumors, therapy is still often debilitating and unsuccessful. There is a pressing need for less toxic and more effective treatment regimens. But in order to develop new therapeutic approaches researchers need good models on which to test hypotheses. Tumor cell lines are used, but these don't accurately replicate the development of human cancer in vivo. Mouse models are also commonly used, but often display physiological and/or molecular differences from human tumors.

In this investigation, Dr. Sage is developing a model of human retinoblastoma, the most common eye tumor in children. A tumor suppressor gene called RB was first identified in families with children who develop retinoblastomas, and since that discovery, RB mutations have been found in other pediatric cancers, as well. This suggests that RB could serve as an important research model. In this study, researchers will create the RB mutation from embryonic stem cells in culture and inject them into a mouse eye to create a model to study the progression of the tumor formation. This information may lead to not only new therapies for retinoblastoma, but other childhood cancers as well.

Hugo Caldas, Ph.D.
Wake Forest University Health Services
Targeting the Angiogenic properties of Survivin ΔEx3 in Medulloblastoma

In previous research, Dr. Caldas demonstrated that Survivin is a member of class of proteins that inhibits apoptosis—the natural act of cell death that helps the body rid itself of abnormal cells. Survivin is abnormally activated in tumor cells, but is silent in most normal cells. Dr. Caldas also found that one type of the protein, called Survivin ΔEx3, is involved in angiogenesis, a key physiologic process that results in the formation of new blood vessels that feed cancer cells. In this new research study, Dr. Caldas is hoping to use a specific short "interfering RNA" to target Survivin ΔEx3 produced in the blood vessels within pediatric brain tumors. This research may lead to a promising new approach to the treatment of malignancies by blocking Survivin in the vessels of tumors.

Alejandro Sweet-Cordero, M.D.
Stanford University
Identification of novel therapeutic targets and prognostic markers of Ewing's sarcoma

Ewing's sarcoma is one of the most common solid tumors in children. While the cure rate for this disease has improved, children with Ewing's sarcoma that has spread beyond the initial site often don't survive. Current treatment regimens are very toxic, decreasing a child's quality of life during and after treatment. However, research has shown that a molecular lesion called a translocation exists in Ewing's sarcoma. In translocation, two chromosomes break and then fuse back together abnormally. In the case of Ewing's sarcoma, the most frequent translocation fuses together a gene called EWS with a gene called EWS FLI-1. This leads to the production of a protein that causes cells to proliferate and become cancerous.

In this study, Dr. Sweet-Cordero is working to identify those genes that are crucial in enabling EWS FLI-1, and which might prove to be an effective target for therapy. Using gene array expression, Dr. Sweet-Cordero is also working to develop methods to help identify patients with Ewing's sarcoma who are likely to respond to chemotherapy and who will not. This could lead to the development of a gene expression "signature" that would predict chemotherapy response in patients.

Utpal P. Davé, M.D.
Vanderbilt University Medical Center
Identification of genes cooperating with LMO2 in T-cell leukemia

Acute Lymphoblastic Leukemia (T-ALL) is the most common form of cancer in children. Like most cancers, it is caused by mutations in genes that regulate crucial cell functions such as growth, signals for self-destruction, and invasion into normal tissues. In this study, Dr. Davé is examining the genetic changes that cause leukemia. Previous studies in mice have shown that leukemia develops as a result of repeated bouts of infection by retroviruses, which insert themselves into genes. In some instances, the retroviruses activate or disrupt neighboring genes. This mechanism has also been seen in human cancers. Animal studies also uncovered two genes—LMO2 and IL2RG&meash;that are the frequent targets of insertion. Researchers hypothesize that the development of T-ALL requires that both of these genes be deregulated. In this project, Dr. Davé is studying this phenomenon in mice. His research results may enhance our understanding of the causes of leukemia and provide novel targets to be used in diagnosis and treatment.

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