Grants Search Results

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.

Adolescents with cancer experience many symptoms resulting from their disease and its treatment. Recognizing and managing these contributes to improved quality of life during treatment and on into survivorship. This study uses an approach that allows adolescents to identify clusters describing their symptom experience from their perspective. The purpose is to develop and test the use of a computer-based tool exploring symptom clusters among adolescents with cancer. The goal of these findings is to provide data to support use of the tool in a larger group of adolescents and to enhance communication between them and healthcare providers.

Myelodysplastic syndrome (MDS) is a blood cancer that affects the bone marrow stem cell and may lead to acute leukemia. Pediatric MDS is rare and causes are unclear, although associations exist with inherited bone marrow failure syndromes. Diamond-Blackfan anemia (DBA) and Shwachman-Diamond syndrome (SDS) significantly predispose to MDS and are linked with disruption of an important organelle in the cell called the ribosome. This new consortium of clinical and basic researchers is studying the biology of pediatric MDS associated with ribosome dysfunction. This project is directly relevant to finding therapeutic targets for MDS, a devastating and understudied form of blood cancer in children. Funds administered by the Feinstein Institute for Medical Research.

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.

Neuroblastoma can range from spontaneous regression to relentless progression. Clinical and biological prognostic factors are used to classify patients as low-, intermediate-, or high-risk of relapse, to determine the intensity of treatment necessary. Recently, several investigators have published "genetic signatures" that correlate with outcome in children with high-risk neuroblastoma in retrospective studies, but due to expense, timing and availability, these signatures are not currently used. This project aims to circumvent these limitations, improving the care of the 40% of high-risk patients who are destined to fail current therapies. Awarded at The University of Chicago and transferred to Dana-Farber Cancer Research Institute. 

Based on progress to date, Dr. Mullighan was awarded a new grant in 2014 to fund an additional two years of this Scholar award. Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and still the most common cause of cancer related death in children. This project uses cutting-edge genetic profiling approaches to identify all genetic alterations contributing to the pathogenesis of high-risk childhood leukemia. This project uses detailed genomic analysis coupled with the development of experimental models of ALL that examine the role of newly identified genetic alterations in the development of leukemia, and response to therapy.  

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.

Significant challenges remain in the treatment of leukemia that has infiltrated into the central nervous system (CNS). The CNS serves as a sanctuary site for leukemic cells which can relapse and spread to other organs. In particular, T-cell ALL, a sub-type of acute lymphoblastic leukemia (ALL), has a strong propensity to infiltrate the CNS. Dr. Othman's research focuses on a recently identified target protein, CDK5, which has been implicated in the migration of immune cells. These potentially paradigm-shifting investigations promise the development of new biological agents or immune-mediated therapies against CNS leukemia and other devastating childhood tumors of the brain.

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.  

Transfusions with packed red blood cells (PRBCs) are commonly used when children treated for cancer develop anemia (low red blood cell count). PRBC transfusions carry iron that can be deposited in various body tissues, such as the heart. The body cannot remove this iron overload by itself, and if it stays in the heart, it can cause damage (cardiomyopathy). At this time, we do not know how often patients have extra iron in their heart after PRBC transfusions. This study uses a magnetic resonance image (MRI) test that can measure iron and learn about other things that might affect the heart, such as anthracycline chemotherapy and what effect iron-related cardiomyopathy has on daily life. The overall goal is to increase the length and quality of survival for people successfully treated for cancer during childhood.

Neuroblastoma is the second most common solid cancer in children, and only 45% with high-risk disease are cured. The goal of the New Approaches to Neuroblastoma Therapy (NANT) consortium is to develop and test new therapies with high potential for improving survival. NANT links laboratory and clinical investigators to develop therapies that are tested at 16 North American neuroblastoma centers. Studies are supported by the NANT Operations Center at Children's Hospital Los Angeles. Studies test two new ways to improve elimination of small amounts of tumor cells that remain after high-dose chemotherapy. Funds administered by Children's Hospital Los Angeles.

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.  

Leukemia, a cancer of the white blood cells, is the most common cancer in children. While a majority can expect to be cured with chemotherapy, a significant number either never go into remission, or relapse. One theory as to why certain leukemias do this is that normal, non-cancerous cells in the bone marrow can help small populations of leukemia cells evade chemotherapy-induced death, leading to relapse. This research project focusing on a protein called CXCR4, is to find a way to make chemotherapy more effective and may lead directly to clinical trials in children with high-risk leukemias that will improve cure rates.

Based on progress to date, Dr. Skiles was awarded a new grant in 2013 to fund an optional third year of this fellowship. Vincristine is one of the core anticancer agents used in many childhood cancers. It is associated with cumulative dose-dependent neurotoxicity, often making it necessary to reduce chemotherapy dosage, compromising effective treatment. There is substantial variability in the way vincristine is metabolized from one person to the next. For example, Caucasians develop neurotoxicity much more frequently than African-Americans, probably as a result of genetic differences in a specific drug-metabolizing enzyme. This is of particular importance in African populations where the treatment outcome is poorer than in U.S. populations. Currently, drug dosing recommendations used in Kenya are based on dosing schemas derived in primarily Caucasian patient populations. This study helps develop individualized vincristine dosing parameters based on genetic predictors, which may lead to improved cure rates, as well as less neurotoxicity in long-term cancer survivors both in the U.S. and in Kenya.

Failure to improve survival of children with brain tumors and minimize permanent and sometimes devastating treatment toxicities reflect the inadequate understanding of the biology and epidemiology of pediatric brain tumors. One of the major obstacles in pediatric brain tumor research is the limited number of patients and tumor samples. By forming a consortium of prominent pediatric neuro-oncology cancer centers in Texas and Oklahoma (Texas-Oklahoma Pediatric Neuro-Oncology Consortium; TOPNOC), these researchers are pooling tumor samples and scientific expertise to conduct innovative, biology-driven clinical trials to improve survival in children with brain tumors. Funds administered by Baylor College of Medicine.

Bone marrow transplantation is an important and potentially curative treatment for children with relapsed leukemias. Infections due to a delay in the recovery of the immune system after transplantation are a major cause of complications and even death in these children. T-cells are a type of immune cells that fight infection. Of the various components of the immune system, the T-cells are the one that recover the poorest after bone marrow transplantation. The aim of this project is to understand how VEGF improves T cell production, with the ultimate goal of improving cure rates for children with relapsed leukemias.

Research in the last 30 years has had a wonderful impact on the survival rate of kids with many types of cancers. However, aggressive treatment regimens on children's young bodies have many negative side effects. One class of chemotherapy drugs, anthracyclines, have been used to effectively treat more than 135,000 childhood cancer survivors, but cause significant risk for cardiovascular disease by the time these children reach their 30s. This research will use Cardiac Magnetic Resonance Imaging and chemical markers in the blood to identify heart damage caused by anthracyclines before symptoms begin, thereby reducing long-term life-threatening heart conditions for pediatric cancer survivors.