Childhood Cancer Research
Children’s Hospital of Philadelphia
3401 Civic Center Boulevard
Philadelphia, PA 19104
United States
Background
Cancers arise because of mutations (or mistakes) in their genes. For many cancers, the identification of their most important cancer genes, and an improved understanding of how these effect the cancer cells, has led to new treatments. Neuroblastoma is a childhood tumor that is often difficult to cure.
Background
Despite the fact that cooperative group oncology trials have improved overall survival for children with cancer, investigators face significant challenges in conducting trials. This application seeks to develop novel data sets to improve the effectiveness of cooperative use trials by using administrative clinical data from approximately 100 hospital sites. Administrative clinical data contains an enormous wealth of information and its value has only recently begun to be realized in health-based research.
Dr. Schnepp has joined the Department of Pediatrics at Emory University and is a member of the Aflac Cancer and Blood Disorders Center in Atlanta, GA.
Background
Children with Down syndrome (Trisomy 21) exhibit numerous blood abnormalities and a predisposition to leukemia. Neonates with Down syndrome are often born with a pre-leukemia termed transient myeloproliferative disorder (TMD). Many subsequently develop acute megakaryoblastic leukemia (AMKL) by age 4 which is associated with significant treatment-related toxicity. Both TMD and AMKL are accompanied by mutations in a gene named GATA1 that is required for normal blood development.
Effects of treatment for childhood cancer can profoundly affect daily activities and quality of life for children and their families. By nature, children explore their lives through play and activity. Health changes that include pain, fatigue and loss of appetite experienced during cancer treatment can negatively affect children's ability to participate in activities.
Acute lymphoblastic leukemia (ALL) is the most common cancer of childhood. Despite significant advances in curing ALL in most children, approximately 20% of these patients will relapse, and nearly all relapsed patients will die from their leukemias. Our research focuses upon studying blood and bone marrow samples from children with certain types of high-risk ALL with the goal of improving our understanding of the functional consequences of specific genetic mutations.
Neuroblastoma (NB) is the cancer of the immature nerve cells. It affects mostly infants and children and, with the exception of brain tumors, is the most common solid tumor of the childhood, accounting for approximately 15% of all pediatric cancer deaths. Although some of the tumors dissolve spontaneously, for patients with high-risk neuroblastoma survival remains well below 40%, despite aggressive and rather debilitating therapy. This necessitates the development of new targeted therapies.
The failure of cancer treatments to kill tumor cells, called therapy resistance, is responsible for most childhood cancer deaths. The precise mechanisms for this resistance are obscure, but most are thought to disrupt death signals that should be “turned on” when sufficient cell stress is encountered. A family of Bcl2-homology (BH) proteins are responsible for responding to chemotherapy- or radiation-induced stress to activate such a death signal. Accordingly, cancer cells typically alter their BH proteins to block these death signals, leading to resistance.
Cancer-promoting genes (a.k.a. oncogenes) are often overexpressed via a translocation to a different chromosome or an increase in gene copy number. Yet for many oncogenes there are no known mechanisms of overexpression, one textbook example being IGF1R. This suspected oncogene is highly overexpressed in most malignant tissues but is seldom a target for chromosomal abnormalities. Attempting to identify an alternative mechanism, we considered that gene activity could be effectively controlled by microRNAs (miRs).
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