Childhood Cancer Research
Children’s Hospital of Philadelphia
3401 Civic Center Boulevard
Philadelphia, PA 19104
United States
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).
Low-grade glioma is one of the most common types of brain tumor that occur in children. Until recently, little was known about the molecular events that led to glioma formation. As a direct result of this paucity of information, low-grade glioma directed treatment has significantly lagged behind advances made in other childhood malignancies. Children with unresectable or recurrent/disseminated low-grade gliomas have been left with few treatment options. Their event free and overall survival rates have been dismal.
Children’s Hospital of Philadelphia
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. While current therapies have resulted in significant improvements in survival, relapsed ALL does not usually respond to chemotherapy. If a child does eventually respond to more intensive chemotherapy, bone marrow transplant offers the best chance for cure, although with significant risks of severe illness or death.
Disease-specific research teams at the Children's Hospital of Philadelphia (CHOP) have been successful in bench to bedside work, having identified key molecules involved in the genesis of neuroblastoma, and subsequently having studied agents that target these molecules in preclinical and clinical settings. From a programmatic point of view, it is logical to build upon this success and apply the bench to bedside paradigm beyond the disease-specific setting.
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