Past Recipients - 2008

New York University - Langone Medical Center
New York, NY
Severine Cathelin, Ph.D

Acute Lymphoblastic Leukemia (ALL) is the most common pediatric malignancy. Despite advances in the treatment methodology used in the childhood ALL, multiple important mechanistic and therapeutic questions remain to be answered in order to improve current therapy protocols and patient survival rates.T-ALL is infrequently associated with chromosomal aberrations. The etiology of this disease remained enigmatic until the recent discovery of Notch1 mutations in the majority of T-ALL patients making Notch1 the major oncogene in the T-ALL. This discovery fueled an effort to understand Notch1 function in leukemia and identify pharmacological interventions that block its activity.

We have recently discovered that the NF-kB signaling pathway as an important downstream target of Notch1 activation. In this research proposal I directly address the importance of the NF-kB signaling pathway in the T- cells transformation and suggest therapeutic approaches that could affect disease progression and patient survival. The first objective of my studies is to study the role of the NF-kB pathway in the Notch1-mediated leukemia. I will silence the NF-kB pathway using a mouse model of T-ALL, and study effect of NF-kB pathway deletion in induction and development of Notch1-mediated leukemia. The second objective is to check that the inhibition of NF-kB pathway is a powerfull therapeutic approach for the treatment of T-ALL. I will generate mouse models of T-ALL that can be used for preclinical drug screening and I test whether pharmacologic inhibitors of NF-kB signaling can suppress the development of the T-ALL in this mouse model.

Stanford School of Medicine
Stanford, CA
Peiyun Chang, Ph.D.

Our genomic DNA contains instructions to build our bodies. However, cells can display distinct phenotypes though they share the same DNA sequence. "Epigenetic mechanisms" contribute to these phenotypical changes that are not explained by DNA sequence changes alone. Unfortunately, these "epigenetic mechanisms" are often mis-regulated in cancers, such as leukemia and lymphoma. Inappropriate expression of genes that normally promote growth help cancer cells divide uncontrollably. Epigenetic regulation in human cells involves several crucial factors including the notorious MLL (Mixed Lineage Leukemia) protein. MLL is mutated in at least 80% of leukemias arising in infants and a majority of secondary leukemias (arising in patients previously treated with chemotherapy). The goal of this proposal is to understand the normal and oncogenic functions of MLL, focusing on its protein domains.

Dana-Farber Cancer Institute
Boston, MA
Simone Hettmer, M.D.

Rhabdomyosarcoma is the most common soft-tissue cancer in children and adolescents. It comprises different subtypes characterized by distinct patterns of presentation and differences in outcome. Alveolar rhabdomyosarcoma, one of the two major subtypes, continues to be a formidable challenge because of its highly aggressive behavior, poor response to current therapies and dismal outcome. The need is pressing, therefore, for a better understanding of the development of this cancer. Rhabdomyosarcoma resembles developing muscle tissue, and it is likely to arise from cells that belong to the family of skeletal muscle cells. However, the precise cell type(s) from which rhabdomyosarcoma originates remain unclear. To identify the cell type(s) that give rise to rhabdomyosarcoma and perpetuate the disease, we propose a novel approach based on our recently developed strategy to isolate distinct groups of muscle-associated cells from freshly dissected mouse muscle. Muscle-associated cells are isolated in a prospective manner so that they are available for direct study. As part of this proposed work, distinct groups of muscle-associated cells with specific functional properties and origins during development will be genetically altered and re-injected into recipient animals in order to test which group/ cell type(s) grow into rhabdomyosarcoma tumors and perpetuate the disease. We will then use large-scale genomic screening tools to investigate differences between these cells and their normal counterparts. Findings from this proposed work will clarify our understanding of the interplay between genetic changes and cellular contexts in early cancer development/ progression, and thereby facilitate the development of new treatments for rhabdomyosarcoma.

Cincinnati Children's
Cincinnati, OH
Kevin Link, Ph.D.

Acute leukemia impacts adults and children of all ages with 18,610 new cases and 10,410 deaths estimated this year. Although therapies are improving for these diseases, much remains to be understood in order to develop more effective and longer lasting treatment options. Our lab is committed to finding better therapeutic options as demonstrated through the unique model systems that we have generated. Unlike most leukemia model systems, the system in our lab uses human cells that can be manipulated into resembling actual human leukemia. These cells are transformed with a common gene abnormality (MLL-AF9) seen in both myeloid and lymphoid leukemia, two of the major types of leukemia. Depending on the growth conditions that we use, the cells can be forced to resemble myeloid or lymphoid acute leukemia. Additionally, this system can be utilized to initiate either type of leukemia in a mouse model system that, again, highly recapitulates the human disease. The proposal herein will take full advantage of what this system has to offer. Based on current literature and our preliminary data, we have chosen to examine a signaling pathway (FLT3 tyrosine kinase) that often becomes deregulated in leukemia, including the leukemia we successfully model in our laboratory. We propose to determine the stage at which the signaling is deregulated and the specific signals that are important in this activation. This will provide necessary knowledge for the identification of alternative targets for treatment of leukemia harboring deregulation in this signaling pathway. Given the close similarities between our laboratory model system and what is actually seen in human patients, the results from this proposal should provide valuable information in selecting chemotherapeutic treatment options for patients suffering from the highly common leukemia subtypes that we will examine.

Vanderbilt University
Nashville, TN
Ling Yan, Ph.D.

The FOXO family genes are cancer genes in childhood malignancies. Abnormalities in FOXO genes cause leukemias and muscle cell tumors called rhabdomyosarcomas. The normal function of FOXO genes is to protect against tumors by causing undesirable cells to die and preventing unwanted cell proliferation. Much recent work have demonstrated that FOXO genes are very important in many cancers, including work showing that mice lacking FOXO genes develop spontaneous tumors. FOXO proteins exist as active and inactive forms. Inactivation of FOXO promotes tumors, while activation of FOXO is protective against tumors; therefore activated FOXO is desirable. We are interested in studying what causes FOXO to switch from the inactive to the active form in order to understand how FOXO proteins work to inhibit tumors. We have already found two molecules that control FOXO activity, and we wish to further elucidate the details of how these molecules work to prevent tumor formation. This research will help us understand how childhood tumors are formed when FOXO genes are not working correctly. The information gained can also be used to design drugs, which can activate FOXO to induce tumor to cells die or stop proliferating, when conventional therapies fail. The long-term goal of our work is to help cure childhood tumors.

Baylor College of Medicine
Houston, TX
Jason Yustein, M.D., Ph.D

Ewing's sarcoma is the second most common bone tumor in the pediatric population. It is a highly malignant tumor for which our understanding of the biology and production of novel treatments has been extremely disappointing. Overall survival for this disease has not significantly improved over the past two decades and, therefore, it has become evident that a better understanding of tumor biology and the molecular mechanisms contributing to the disease manifestation are vital to eventually improving patient survival. Ewing's sarcoma is defined by a characteristic novel protein found to be uniquely expressed and crucial for the development of this tumor. This protein, known as EWS-Fli1, is a transcription factor that regulates numerous genes vital to the tumor initiation and growth. Transcription factors control the expression of all of the genes in our cells and, in many cancers it is the abnormal expression and regulation of particular genes that leads to tumor formation. Interestingly, one of the genes that this novel protein increases is another tumor promoting gene, c-MYC. Myc is a well-known tumor promoting gene (aka oncogene), which is also a transcription factor known to be deregulated in numerous malignancies. The genes it regulates have numerous cellular functions ranging from controlling cell growth, proliferation and death. Thus, understanding the role this oncogene plays and the genes that are controlled by c-Myc within Ewing's sarcoma may provide new insights into key cellular pathways and mechanisms required for tumor growth, which may identify novel potential targeted therapies.

UCSF Children's Hospital
San Francisco, CA
Steven DuBois, MD

Ewing sarcoma is the second most common bone cancer seen in children and young adults. Approximately 75% of patients are diagnosed with tumors that have not yet spread, or metastasized, to other parts of the body. Using a laboratory technique called PCR, researchers have shown that many of these patients have tumor cells in their blood and bone marrow. These tumor cells may go on to develop new tumors elsewhere in the body. While PCR is a good test, there are several problems with using PCR to measure Ewing sarcoma tumor cells in the blood and bone marrow. We have developed a new laboratory technique to measure Ewing sarcoma tumor cells in the blood and bone marrow. This method uses a machine called a flow cytometer to measure a specific protein, known as CD99, which is present on the surface of almost all Ewing sarcoma tumor cells. In this study, we plan to study 20 patients with Ewing sarcoma over 2 years. We will collect a sample of their blood and a sample of their bone marrow. We will use both the PCR method and our new flow cytometry method to find Ewing sarcoma cells in these samples. We hope to show that this new flow cytometry method can find Ewing sarcoma cells in these samples as accurately and effectively as the current PCR method. In the future, this technique may be useful to monitor the disease burden and effectiveness of therapy in Ewing sarcoma.

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