Grants Search Results

Based on progress to date, Dr. Gershon was awarded a new grant in 2014 to fund an additional two years of this Scholar award. Medulloblastoma strikes the cerebellum, a brain region that sees rapid growth after birth, as special cells called progenitors divide repeatedly, increasing the number of brain cells. Gene mutations that allow unrestricted progenitor growth cause medulloblastoma. Understanding which genes control progenitors, and how these genes work together, may lead to new medulloblastoma treatments. Dr. Gershon is investigating a previously unknown connection between the immune system, brain growth, and the formation of brain tumors, and a novel way to use developmental biology to treat medulloblastoma.  

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.  

The treatments used to cure pediatric cancers can cause infertility. Banking sperm at diagnosis is the gold standard for preserving fertility for boys who have reached puberty, but is not an option for younger boys who do not yet have mature sperm in their testicles. The prepubertal testicle does contain a small number of stem (parent) cells that will eventually become mature sperm, so one new idea is the use of testicular tissue frozen at diagnosis, then later thawed with the parent cells reimplanted into the testis to mature or matured outside the body and then used with assistive reproductive techniques. This consortium is collecting testicular tissue samples to increase the amount of tissue available for research, in the hope of providing an option for fertility preservation to patients who currently have no options at all.  Funds administered by the Children's Hospital of Philadelphia.

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.  

Neuroblastoma is the second most common solid cancer in childhood. Half of patients are at an advanced stage at diagnosis, difficult to treat successfully even with aggressive therapy. Ferritin is the body's storage form of iron, and elevated levels have been linked to worse outcomes in patients with neuroblastoma, but this phenomenon is still poorly understood. This research is investigating how genetic mutations in HFE, the gene responsible for the iron overload disorder, promote the development and spread of neuroblastoma cells. By identifying which specific iron metabolism pathways are involved, we can come up with new therapeutic strategies that are more specific and less toxic.

To identify new therapeutic approaches in high-risk childhood acute lymphoblastic leukemia (ALL), this consortium of investigators has performed detailed analysis of genetic mutations in high-risk ALL. Pilot studies have identified over 40 new mutations and chromosomal rearrangements, several of which may be targeted by new treatment approaches. Following this, the group is performing mutation testing of larger numbers of childhood ALL samples to learn the nature and frequency of these mutations. This is the most comprehensive survey of genetic changes in childhood leukemia to date, and is likely to provide crucial new insights into the biology of this disease. Funds administered by the University of California, San Francisco.

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.

Based on progress to date, Dr. Kim was awarded a new grant in 2014 to fund an additional two years of this Scholar award. Despite the recent advances in chemotherapy for acute lymphoblastic leukemia (ALL), drug resistance often results in relapse of ALL. Preclinical studies have shown that leukemia cells can evade chemotherapy as they are protected by their bone marrow environment. This study proposes to dislodge chemo-resistant cells from the protective bone marrow making them vulnerable to chemotherapy. We propose to study the functional role of CD49d in drug resistant leukemia and will validate it as a potential, novel target for treatment of recalcitrant childhood ALL.

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.