The long-term goal of this program project is to improve cure rates among children with malignant solid tumors, especially rhabdomyosarcoma (RMS), Ewing sarcoma and osteosarcoma.
This aim will be pursued by a coordinated multidisciplinary effort, consisting of 7 projects and a CORE. The major thrust will be to develop new agents and strategies designed to overcome problems of drug resistance. Project 1 will address the efficacy of 5- fluorouracil-leucovorin interactions in xenografts of previously untreated osteosarcoma. Project 2 deals with nucleoside transport in normal and RMS cells to define differences that could lead to the development of improved treatment strategies. Project 3 will investigate rhabdomyoblast differentiation and drug binding with use of the 5.1 H11 monoclonal antibody, both in vitro and in vivo. If binding is specific, the antibody will be conjugated to vincristine in an effort to """"""""target"""""""" the delivery of this agent. Project 4 will examine the interaction of VP-16, antimicrotubule compounds and ifosfamide in treatment of RMS and Ewing sarcoma in vitro, and subsequently in vivo. Project 5 will attempt to clarify the mechanisms of cross resistance between vincristine and the bifunctional alkylating agent melphalan in RMS xenografts. Project 6 examines the potential role of DNA repair in the acquisition of resistance to the alkylating agents by RMS and Ewing sarcoma cells. Project 7A applies genetic techniques to the analysis of solid tumor cells with the aim of refining clinical staging systems. Pharmacokinetic studies (Project 7B) will be an integral part of phase I and II clinical trials and preclinical investigations in experimental models. Further, we plan to test alternative agents in previously untreated patients with advanced RMS, osteosarcoma and Ewing sarcoma (Project 7D). These """"""""phase II-III pilot"""""""" studies should permit truer estimates of drug activity than can be gained by conventional means. Another novel aspect of this program is the use of human tumor xenografts to evaluate the activity of new agents prioritized by considering data from Project 1-6 or from extramural phase I or II trials. The information gained will supplement or supercede data from classic phase II trials in determining drug evaluation priorities for phase II-III pilot studies, since the former are often performed in heavily pretreated patients with resistance to multiple agents. Centralized support (e.g., biostatistical consultation and data management, program administration, and xenograft models) are provided within the CORE. The research program outlined here should provide new information regarding genetic staging and mechanisms of oncogenesis, and serve as a paradigm for developmental therapeutics in pediatric solid tumors.
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