The Pharmacology & Experimental Therapeutics (PET) Section focuses on the selection and clinical development of new agents for the treatment of childhood cancers and the study of the pharmacokinetics and pharmacodynamics of anticancer drugs. The central nervous system (CNS) pharmacology of anticancer drugs is also studied because of the high incidence and dire consequences of primary and metastatic CNS cancers in children. The Section has developed an integrated research program that includes preclinical models to study the pharmacology and applications of new agents in childhood tumors and an active clinical trials program to study the toxicity, activity, pharmacokinetics and pharmacodynamics of these agents in children.Clinical trials are performed as single institution studies or collaboratively with other children's cancer centers or cooperative groups. A variety of agents are studied, including cytotoxic drugs, molecularly targeted drugs, antiangiogenic agents, and drugs that modulate the therapeutic or toxic effects of anticancer drugs. The pharmacokinetics and pharmacodynamics of new agents are studied in preclinical models and in patients entered on clinical trials. The Section works with the Cancer Therapy Evaluation Program and the pharmaceutical industry to ensure that promising new drugs are studied in children. The Section is currently a non-funded member of the COG Phase1/Pilot Consortium and COG. This has allowed the movement of agents studied in phase I trials in the Section (e.g., ABT-751, ixabepilone) into phase II trials in the cooperative groups. Preclinical models, such as the drug development tissue microarray are being developed to aid in selecting the new molecularly targeted drugs that are best suited for development in childhood cancers.The CNS pharmacology of anticancer drugs is studied in a non-human primate model with indwelling ventricular catheters that allow for sampling of the cerebrospinal fluid (CSF) and drug administration into the lateral ventricle. Drug penetration into the CSF, which serves as a surrogate measure of blood-brain barrier (BBB) penetration, is used to identify potential new drugs for CNS tumors. Microdialysis is also used to measure extracellular fluid drug concentration in brain tissue and to relate brain drug concentration to the drug concentration in other tissues and the cerebrospinal fluid. In addition, strategies to pharmacologically modulate the BBB have been investigated in this model. The preclinical and clinical development of new agents that can be administered intrathecally for the treatment of meningeal tumors is also a focus of research.The PET Section provides pharmacokinetic support for clinical trials in the CCR, including designing clinical pharmacokinetic studies, the development of drug assays and the measurement of drug concentrations in patient samples, and the analysis of pharmacokinetic data generated by our Section or by pharmaceutical companies. The Section will explore the use of microdialysis as a tool to measure drug exposure in tumors and the blood of patients receiving anticancer drugs.
Showing the most recent 10 out of 32 publications
