The applicant, Dr. Rochelle Bagatell, is a pediatric oncologist who is committed to pursuing a career in patient oriented research, with a focus on the study of molecularly targeted therapies for pediatric cancer. Several agents that target signal transduction pathways in tumor cells have been found to be effective in the treatment of cancers in adults, but these agents have not been widely studied in children. Given the dismal prognosis for children whose malignancies recur following intensive therapy, newer and less toxic drugs are needed. One effective approach to inhibiting signaling pathways that promote cancer cell survival could be provided by drugs that alter the function of heat shock protein 90 (Hsp90). Hsp90 plays an essential role in stress tolerance, protein folding and post-translational control of the stability and function of many key regulators of cell growth, differentiation and apoptosis. Geldanamycin, the prototype Hsp90 inhibitor, binds to Hsp90 and in so doing causes alterations in levels of key cancer-associated proteins that are regulated by Hsp90. Hepatotoxicity prohibits the use of this agent in vivo, however clinically relevant geldanamycin derivatives are currently in clinical trials. 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17- DMAG; NSC 707545) is a geldanamycin derivative with favorable pharmaceutical properties. Agents of this class are of particular interest in the treatment of pediatric malignancies because they cause a marked decrease in levels of signaling molecules that are important in childhood tumors, however 17-DMAG has never previously been administered to children. As part of an effort to achieve the long-term goal of identifying effective molecularly targeted agents for children with cancer, and to achieve the career development goals of the applicant, this research project has been designed. The specific aims proposed are: 1) To evaluate the anticancer activity of 17-DMAG against pediatric solid tumor cells in vitro and in vivo, and to evaluate changes in levels of key HspQO-related proteins following DMAG treatment. 2) To conduct a Phase I trial of 17-DMAG as a single agent in patients with recurrent or refractory malignancies and to measure changes in levels of 17-DMAG target proteins. Primary objectives of the trial will be to establish the Dose Limiting Toxicity (DLT) and the Maximum Tolerated Dose (MTD) of 17-DMAG in these patients and to assess the extent to which the MTD of this drug alters the levels of Akt, IGF1R, and Hsp72 in blood samples. 3) To evaluate combinations of Hsp90 inhibitors and other anticancer agents in pre-clinical models of pediatric solid tumors, and to investigate the mechanisms underlying augmented anti-cancer effects. The proposed research project is part of a carefully structured and multi-faceted career development plan that focuses on the evaluation of molecularly targeted agents for the treatment of childhood cancers. The applicant will receive didactic training through the K30-supported Arizona Clinical Research Training Program and through courses in Pharmacology and Cancer Biology. She will also gain practical experience in the conduct of translational research and clinical trials, and will perform pre-clinical work that will lay the foundation for future clinical trials with strong translational components. Upon completion of the award period, Dr. Bagatell will be well prepared to move forward as an independent investigator. [unreadable] [unreadable] [unreadable]
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