Developmental Biology and Solid Tumor Program

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The Developmental Biology and Solid Tumor Program has as its central role the improvement in curative therapy for children and adolescents with solid tumors. This objective is facilitated through multidisciplinary translational research, focusing on the identification of novel targets for therapy, understanding growth regulation of childhood solid tumors, mechanisms of drug action, drug resistance, diagnosis and clinical therapy. The program’s members represent 11 academic departments at St. Jude. Our preclinical studies range from development of high throughput screening to identify novel pharmacological probes to validate targets, mechanism based studies using genetically tractable organisms such as yeast for identifying drug targets, and repair processes associated with cytotoxic agents that damage DNA. Studies in mammalian cells involve in vitro culture to determine drug targets, and mechanisms of acquired and intrinsic resistance. In vivo models include panels of xenografts that represent common solid tumors in children and adolescents, and transgenic models produced by collaborators in other programs.

The Program has continually fostered interactions among the basic laboratory investigations in molecular pharmacology, pharmacokinetics and clinical research to inform the design and conduct of clinical Phase I/II trials. The program has developed novel protocols for treatment of high-risk solid tumors such as advanced neuroblastoma, rhabdomyosarcoma, relapsed Wilms tumor and brain tumors. In addition, our studies with the camptothecins, the rapalogs, and other new agents have furthered our understanding on how better to use these agents in children. These protocols have been derived from fundamental studies within the program. In addition, ten St. Jude protocols have been extended to national trials in the Children’s Oncology Group (COG). Information from the clinical trials allows further development and refinement of the preclinical research, leading ultimately to improved therapy. Preclinical and clinical studies will build on the current work with DNA topoisomerase I inhibitors, rapamycins, and start small molecule screens. We will continue to identify genes conferring drug resistance, and evaluate these agents with inhibitors of specific cellular signaling pathways. Studies outlined will develop novel anti-angiogenic approaches to tumor-selective therapy for treatment of high-risk neuroblastoma, and sarcomas.

Alberto Pappo, MD, and Michael A. Dyer, PhD, are co-leaders of the program.

 

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Scientific Report