Overall survival for children with tumors of the central nervous system (CNS) has gradually improved, and 5-year survival now approaches 70%. However, for some tumors, such as diffuse intrinsic pontine gliomas and high-grade gliomas, 5-year survival is less than 10% and little progress in improving this outcome has been made in the past 2-3 decades. The prognosis for children with recurrent tumors is also poor, and few treatment options are available. In addition, we face the challenge of treating patients whose brains are still developing. Although great strides have been made in initiating biological studies of these diseases, we have come to realize that pediatric CNS tumors differ significantly from those found in adults, affirming the need for additional in depth studies specifically in pediatric patients.
The mission of the Pediatric Neuro-Oncology Section is to identify and develop new agents and approaches for treating children with tumors of the CNS in an effort to improve overall survival and quality of life. Our research focuses on ways to overcome obstacles to effective treatment, such as the blood:brain barrier which can block effective drug delivery to the tumor, and drug resistance. Our patients are extensively evaluated and treated at the National Cancer Institute Clinical Center located on the NIH campus, generally in concert with the home (referring) physician. We work closely with physicians in Radiation Oncology (NCI) and neurosurgery (NINDS), who are also located on the NIH campus.
Research projects include:
Project 1: Preclinical and clinical development of new agents
The Pediatric Neuro-Oncology research program is focused on the development of new agents for the treatment of CNS tumors in children. Specific areas of interest include CNS pharmacology, evaluating agents that modulate drug delivery into the CNS, and studying agents that modulate drug resistance. We work closely with the Pharmacology and Experimental Therapeutics Section to evaluate new agents with novel mechanisms of action to the treatment of childhood brain tumors.
The NCI is a special member of the Pediatric Brain Tumor Consortium (PBTC), a group of 9 institutions nationwide dedicated to the study of correlative tumor biology and development of new therapies for primary CNS tumors of childhood. We are also a Phase I institution within the Children’s Oncology Group (COG). Clinical trials for pediatric patients with CNS tumors at NCI are performed as single institution studies or conducted through collaborations with these cooperative groups. A variety of agents are studied, including agents that have recently been, or are concurrently being studied in adults, as well as agents that are being studied initially in pediatric patients.
Project 2: Evaluation of alternate drug delivery techniques
The blood:brain barrier (BBB) is a single layer of endothelial cells that serves to protect the CNS and restricts entry of many chemotherapeutic agents. This can result in inadequate drug delivery to the tumor site, resulting in insufficient drug exposure. We are evaluating the CNS penetration of chemotherapeutic agents and studying different strategies to circumvent the BBB. Studies have included BBB disruption using a bradykinin agonist, p-glycoprotein inhibition, and regional drug delivery. We are collaborating with the Neurosurgery Branch, NIAID, in evaluating convection-enhanced delivery for children with CNS tumors.
Project 3: Non-invasive evaluation of children with brain tumors
Noninvasive assessment of biochemical and physiologic changes occurring throughout the brain may be helpful as trial endpoints and in evaluation of treatment related effects. A variety of imaging methods are being evaluated. We have applied a multislice, multivoxel proton spectroscopy method that was developed at NIH to the evaluation of children with brain tumors, including pontine gliomas. In our initial study, we showed that maximum Choline:N-Acetyl Aspartate (CHO:NAA) ratios in children with recurrent and refractory brain tumors was prognostic.(Warren et al, JCO, 2000)
Clinical studies to evaluate the role of advanced MR imaging techniques, including nuclear magnetic resonance spectroscopy, diffusion-weighted imaging, diffusion tensor imaging and perfusion, and PET as tissue surrogates for childhood brain tumors and biomarkers in clinical trials are currently being performed by our section.