Molecular Pharmacology



Research in this department extends from basic studies of drug action and cell biology, through elucidation of signaling pathways that regulate cellular responses to DNA damage, to preclinical studies that identify and optimize new agents relevant to pediatric cancer. Because many cytotoxic drugs cause dose-limiting myelosuppression, there is increasing interest in ameliorating hematologic toxicity through such approaches as transducing hematopoietic cells with protective genes and pharmacologically blocking drug uptake by normal hematopoietic cells. Work in Molecular Pharmacology has defined the mechanisms of action of drugs that target topoisomerases and has furthered the clinical development of camptothecin drugs that target type I topoisomerase in mammalian cells. These studies have been extended to clinical trials designed in collaboration with the Developmental Therapeutics for Solid Malignancies Program and the Neurobiology & Brain Tumor Program. Our studies identifying growth signals and checkpoint functions that are essential for the proliferation, differentiation, and survival of malignant cells in children are being used to define new targets for drug therapy and novel therapeutic approaches to modulating cellular responses to drugs currently used as anticancer agents.

Model systems comprise the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, Caenorhabditis elegans, mammalian cells, mouse models of human cancer, and childhood cancers grown as xenografts in mice. Our therapeutic studies include gene therapy approaches for inducing tumor-selective activation of antitumor prodrugs and investigation of neural progenitor cells as selective delivery vehicles. These studies have involved close collaboration with members of the Pharmaceutical Sciences, Hematology, and Oncology departments. A result of these collaborations is an ongoing series of novel Phase I and Phase II clinical trials based on biochemical and preclinical studies. The Pediatric Preclinical Testing Program, a National Cancer Institute initiative, was recently established at St. Jude to identify potential novel drugs that can be further evaluated in clinical trials. The program includes researchers from the United States and Australia.

Peter J. Houghton, PhD, is the chair of the Department of Molecular Pharmacology at St. Jude.

 


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