Grants Search Results

Viruses promote many cancers. The first human tumor virus, Epstein-Barr virus (EBV), was discovered in cells of a child with Burkitts lymphoma. Since that time, EBV has been detected in several cancers - particularly of children and adolescents. To greatly diminish the risk of cancer, particularly in high-risk youngsters, this study works on the development of a vaccine that stimulates a robust immune response and blocks EBV infection and/or limits spread within the body, preventing tumor development or the likelihood of recurrence. A recent VLP vaccine has proved highly successful in preventing HPV infection and cervical cancer in young adults. EBV is far more complex, but Dr. Fingeroth is working to creatively modify this unique technology to develop a safe and effective vaccine that protects children and adolescents from EBV-associated malignancies.  

Acute myeloid leukemia (AML) is the second most common leukemia in children, with only about a 50% long-term survival. Among the new agents developed during the last decade, histone deacetylase (HDAC) inhibitors (HDACIs) have shown great potential for the treatment of children with AML. It has been shown that HDACIs can significantly enhance the effectiveness of the main drug used for treating children with AML, but the detailed molecular basis underlying that process is unknown. The goal of this study is to form a solid base for establishing new effective therapies for treating children with AML.  

While significant progress has been made in the treatment of acute lymphoblastic leukemia (ALL), there remain specific anatomical sites into which leukemic cells infiltrate and become very resistant to traditional therapies. One of these sites, the central nervous system (CNS), is particularly challenging to treat. Preliminary studies have identified specific cell types in the CNS that contribute to tumor resistance to treatment. The goal of these studies are to expand this knowledge to contribute to the design of new therapies optimized to meet this important clinical problem.  

Rhabdomyosarcoma (RMS), a malignancy arising from striated muscle, is the most common soft tissue sarcoma in children. Metastatic RMS has a poor prognosis and the different subtypes of RMS vary in their clinical behavior. Epigenetic mechanisms may play a role in the progression or differentiation of RMS, but this has not been well studied in this disease. This project uses a novel assay that has revealed important genetic therapeutic targets in other malignancies. It has the potential to advance understanding and help discover new prognostic or therapeutic targets in RMS.  

This study focuses on neuroblastoma, a childhood cancer in which amplification of the MYCN proto-oncogene is associated with older age, rapid tumor progression, and the worst outcome. High-level expression of MYCN is thought to cause an aggressive behavior of the tumors. Researchers have identified several compounds that can rapidly destabilize the MYCN protein (within a few hours) in neuroblastoma cells, suppressing tumor growth. This research is to better understand the biological functions of MYCN and pVHL and their relationship in neuroblastoma, laying a foundation for therapeutic strategies against the disease.

This research involves primitive neuroectodermal tumors (PNETs). One type of PNET, medulloblastoma, is the most common pediatric brain tumor, but current treatments are limited and often have severe side effects, including lifelong cognitive impairment. A common event leading to PNETs is when cells accumulate too much of a certain gene called N-Myc. Surprisingly, we still do not know how too much N-Myc causes these childhood cancers, but there are clues that excess N-Myc alters DNA structure in normal stem cells of the brain leading them to become cancerous. This research tests this idea by determining how N-Myc acts on DNA in stem cells of the brain leading to medulloblastoma, providing the foundation for new treatments, which are both safe and effective. Because N-Myc is implicated in all PNETs including neuroblastoma, retinoblastoma, and Wilms tumor, these studies have extremely high impact and clinical significance.

Neuroblastoma is one of the most common cancers of childhood, accounting for 15% of pediatric cancer deaths. ALK kinase is a protein involved in signal transduction pathway leading to cell proliferation. Amplification of the MYCN gene is found in 20% of neuroblastoma and results in an especially aggressive cancer. This project is to help understand how these two genetic alterations result in the development and progression of neuroblastoma. The long-term goal is to better understand the biological mechanisms that give rise to neuroblastoma and to develop novel therapeutic approaches.

Osteosarcomas are a devastating pediatric bone cancer for which survival rates have not improved over 30 years. Current treatments remain aggressive and are prone to relapse. A new gene has been identified called Sox2, upon which osteosarcoma cells depend for survival. This project will evaluate whether strategies for blocking Sox2 function in tumors can eradicate the tumor and all residual cells to prevent relapse of the disease. These studies provide a novel basis for the targeted treatment of this childhood cancer and lead to a better understanding of the cancer stem cells that give rise to tumors.  

Each human cancer is driven to be lethal by a different set of tumor specific genetic changes. Discovery of these mutations is leading to new targeted therapies, treatments to neutralize these genetic changes. This research involves a single mutant gene (EWS/FLI1), which is present, in some form, in all Ewing Tumors. In addition to learning more about a particularly critical target of this mutant gene, Dr. May also tests one approach to targeted combination therapy, which could be quickly moved to clinical trials.

Medulloblastoma is the most common malignant brain tumor in children; despite advances in neurosurgery, radiotherapy, and chemotherapy, children with high-risk medulloblastoma have a 5-year survival of only 25%. Effective tools for diagnosing, staging, and monitoring are critically needed for these children. MRI is the current state-of-the-art anatomical imaging modality. PET imaging does not work well in brain tumors. Dr. O'Dorisio is developing a new PET imaging agent that will work well in brain tumors. Using PET and MRI together will help determine when children are responding with the goal of decreasing the amount of radiation therapy for many children with medulloblastoma.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and a leading cause of cancer death in children. The gene HMGA1 causes normal cells to transform into leukemia cells, and blocking HMGA1 kills leukemia cells. Other genes cooperate with HMGA1 to cause leukemia. Dr. Resar is studying agents that block these genes and could be adapted for use in therapy. The goal of these studies are to provide a paradigm for treatment of ALL with microRNA replacement therapy and other small molecules, with plans to translate successful studies to the clinic to improve outcomes for children with ALL.  

The inherited bone marrow failure syndromes (IBMFS) are a group of disorders characterized by cancer predisposition. The study of these rare disorders has historically yielded critical insights into universal molecular pathways that cause cancer in the general pediatric population. A common feature of many of the IBMFS is impaired ribosome production or function. Ribosomes were thought to have only a housekeeping role in cells, but recent studies show that alterations in protein translation resulting from ribosomal abnormalities can promote cancer formation. There is an urgent need to better understand this connection. This project evaluates how changes in ribosome function alter protein translation to promote pediatric cancer formation.

The risk of relapse in non-Hodgkin lymphoma (NHL) patients could be related to the ability to completely kill all NHL cells in the body. An international intergroup (US and Europe) non-Hodgkin lymphoma (NHL) treatment trial for children and adolescents will be open at Children's Oncology Group (COG) sites. This study aims to determine if remaining lymphoma cells (residual disease) have been killed, which requires special techniques.  

MicroRNAs are small regulatory molecules that play important roles in tumor formation. Retinoblastoma (RB) is the most common malignant tumor of the eye in childhood cancer. The role of microRNAs in RB remains unclear, but a group of microRNAs that are highly expressed in the early embryonic retina and known to promote cellular proliferation and survival and cancer formation, are highly expressed in RB cells. These miRNAs may be novel therapeutic targets for the treatment of RB. If so, this project could define new therapeutic targets for treatment of RB and may also have important implications for other types of pediatric tumors.

Dr. Yu has recently reported a major breakthrough in the treatment of neuroblastoma with anti-GD2 antibody and cytokines, but the treatment is accompanied by serious side effects including allergic reaction. This project is to test a possible reason for this reaction, using blood samples from patients enrolled in the immunotherapy trials for measurement of anti-sugar antibodies. If the hypothesis is proven true, this research could provide a direction for reducing the toxicities and further improving the outcome of this highly successful immunotherapy.

Neuroblastoma is a cancer that develops in the nervous tissue and most cases occur in children younger than two years old. For patients with high-risk disease overall survival remains poor, thus there is a tremendous need to develop new treatments. This research improves the clinical development of a new drug, MLN 8237, which has shown promise in early pediatric clinical trials, and could improve survival in this devastating disease and provide additional targets for therapeutic intervention.

Sarcomas are aggressive cancers that arise in connective tissues such as skeletal muscle. Approximately 12,000 Americans are diagnosed with sarcoma each year, including a large number of children and adolescents. Even with the most advanced therapies, about half of all sarcoma patients will die from their disease. With past St. Baldrick's support, Dr. Hettmer has identified a subset of genes that are present at increased levels in sarcomas and may serve as new candidate drug targets for these cancers. This project builds on that work, providing essential pre-clinical data on new potential sarcoma therapies, greatly facilitating the ultimate development of treatments for current and future sarcoma patients. Dr. Hettmer is funded by P.A.L.S. Bermuda with funds raised through the St. Baldrick's Foundation.

Resistance to chemotherapy is a great challenge in the cure of cancer. A large proportion of such resistance occurs because of p53 mutations in the tumor, the most commonly occurring mutation in cancer. Dr. Kupfer's research involves a virus that appears to cause resistant p53 mutant cells containing a particular protein to become sensitive to chemotherapeutic drugs. A large library of small molecules will be screened to identify a substance that can mimic this effect, with the ultimate goal of developing a drug that can overcome resistance to chemotherapy.  

Lymphoblasts infiltrate the central nervous system (CNS) in about 30% of children and adolescents with acute lymphoblastic leukemia (ALL), leading to relapse in the brain and spinal cord. While aggressive CNS therapy involving high-dose chemotherapy with radiation has been successful, many patients have significant problems with long-term effects, including a much higher risk of a second cancer and long-term deficits in cognitive function and development. This research is to discover unique aspects of the biology and pathogenesis of leukemia, with a goal of finding new therapeutic targets that can be tested in future clinical trials.  

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, and relapsed ALL is the most common cause of death in children with cancer. The goal of this research is to use technical breakthroughs in human genomics to discover the underlying biological pathways involved in relapse. These discoveries will also potentially inform future treatment studies. Dr. Hogan was a St. Baldrick's Fellow and now has a faculty position.