The objective of this proposal is to enable investigators at Children's National Medical Center (CNMC) to conduct investigations of the therapy, biology, and causes of malignant disease in infants, children and adolescents through participation in the Children's Cancer Group (CCG) and to provide scientific and administrative leadership of such studies. We propose to enter all eligible patients on Groupwide studies of multimodality therapy of acute leukemia and solid tumors. We propose to develop and conduct limited institution pilot (toxicity and/or feasibility) studies incorporating novel treatment strategies for childhood ALL, and dose-intensified treatments incorporating hematopoietic growth factors and stem cell transplantation. We propose to develop and conduct limited institution pilot studies of new agents and novel therapeutic approaches for the management of brain tumors and will continue to design and conduct clinical trials which pose questions of CNS pharmacologic interest. CNMC will continue as the most active CCG institution in the evaluation of new agents, both cytotoxic and biologic. We will participate in correlative pharmacology and biology studies. We will comply with protocol-specified therapy as well as required evaluations and will submit complete and accurate data to the Operations Office in a timely fashion. CNMC will continue as a performance site of the CCG ALL Biology Reference Laboratory for the identification of appropriate patients for biotherapeutic studies incorporating monoclonal antibodies to leukemia cell associated antigens to identify specific immunotoxins for immunotherapeutic classes of disease. This laboratory will lead the effort to evaluate the efficacy of new classes of agents in acute lymphoblastic leukemia using a variety of preclinical models. Laboratory studies of the significance of the expression of the mdr-1 gene at diagnosis and correlation with functional assessment of multidrug resistance and clinical outcome will continue in homogeneously treated patient groups. We propose to continue investigation of the biological significance of shed tumor gangliosides in neuroblastoma, as well as the evaluation of differences in neuroblastoma membrane ganglioside patterns between patients identified through screening programs and patients with overt clinical disease. We propose to participate in case controlled epidemiologic studies of childhood cancer to investigate the possible relationship between genetic predisposition and pre- and post-natal environmental factors on the development of specific malignancies. We will participate in the formulation and conduct of quality of life evaluations to examine the long-term impact of successful anticancer therapy on all aspects of growth and development.
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