Grants Search Results

Based on progress to date, Dr. Chang was awarded a new grant in 2013 to fund an optional third year of this fellowship. Children with Neurofibromatosis Type 1 (NF1) are strongly predisposed to Juvenile Myelomonocytic Leukemia (JMML), a relentless form of cancer. Only 50% of children with JMML survive beyond 5 years, and hematopoietic stem cell transplantation currently offers the only potential for cure, although transplant-related mortality is high. Therapies targeted to specific molecular abnormalities in JMML may offer a better alternative. Ras is a protein involved in normal cellular growth as well as malignant transformation. Understanding the therapeutic effects of inhibiting Ras effector pathways will inform novel treatment strategies.

Cancer is caused by alterations (mutations) in the genetic material of tumor cells. The identification of these mutations has allowed the development of treatments specifically targeted at the mutated genes, resulting in remarkable clinical advances for a few specific cancer types. This proposal uses state-of-the-art sequencing technologies to analyze hepatoblastoma, the most common liver cancer of children. The goal of this project is to dramatically shift current research and treatment paradigms by directing investigators to the most relevant genes causing hepatoblastoma, which are currently largely unknown.  

Diffuse Intrinsic Pontine Glioma (DIPG) and Medulloblastoma (MB) are the two most common malignant brain tumors in children, highly aggressive tumors that cause disability and death. A new concept in cancer biology is the cancer stem cell hypothesis, which states that tumors are initiated and maintained by a small fraction of cells with stem cell-like properties. This hypothesis could explain many of the mysteries of cancer biology, one of them being the recurrence of the same tumor despite aggressive radiation and chemotherapy. This study uses a computer program called MiDReg with DIPG and MB tumor samples to learn more and ultimately develop safer and better treatments.

A growing tumor requires a blood supply, and in some tumors, such as neuroblastoma, the number of blood vessels in a tumor correlates with metastases and mortality. The formation of new blood vessels is called angiogenesis. Anti-angiogenic drugs designed to stop these blood vessels from forming have proved disappointing, so far. The lab in which Dr. Elster is working has identified one reason for this. In this project, known pharmacologically active compounds are screened to find what may be the backbone for the next class of anti-angiogenic drugs.

T-cell acute lymphoblastic leukemia is an aggressive cancer that requires highly intensive chemotherapy, and the prognosis of patients with relapsed and refractory T-ALL is very poor. The genetic lesions responsible for progression and relapse in this disease remain largely unknown. The goals of this project are to identify novel pathogenic genes and pathways in relapsed and refractory T-ALL, to assess their contribution to T-cell transformation and chemotherapy resistance. These results will be ultimately translated in new diagnostic tools to identify high-risk patients and in new molecular targeted drugs for the treatment of this disease.

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.  

Several recent studies have identified point mutations IDH1 and IDH2 in gliomas. IDH are key enzymes involved in cell metabolism. These mutations occur frequently (50-93%) in diffusely infiltrating astrocytomas and oligodendrogliomas, as well as in some glioblastomas. These studies suggest that IDH1 mutations are an early event in the formation of specific types of diffusely infiltrating gliomas, and this project uses a virus to deliver genes to determine if mutant IDH1 can induce brain tumors in models.  

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.  

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.

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.

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.  

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.

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.