The treatment of children with high-risk solid tumors has significant morbidity and relapse or refractorydisease still is the leading cause of death in these children. New therapeutic strategies are needed. Thisproject 5 comprises the clinical Phase l/ll research studies of this Program Project Grant and focuses on 4hypotheses: (1) that approaches to decrease toxicity and increase efficacy of irinotecan administration andthat account for interpatient variability of topotecan will further improve efficacy of these agents, (2) thatinhibition of mTOR signaling will effectively slow tumor growth, sensitize tumor cells to DMA damagingagents, and reduce the rate of drug induced mutations that contribute to drug resistance, (3) that targetingtumor-derived VEGF in concert with reducing levels of circulating growth factor will have greater effect ontumor angiogenesis than targeting only circulating VEGF and (4) that inhibition of mTOR in combination withinhibition of IGF-I receptor signaling will enhance objective responses. Incorporated into selected clinicaltrials will be assessments of the expression of the ErbB family of receptors and BCRP/MRP, and mTORinhibition and recovery. Each clinical trial is derived from observations in laboratory projects.
Aim 1 focuseson the continued development of camptothecins with the evaluation of pharmacokinetically targetedapproach to dosing topotecan in retinoblastoma and the use of oral cefixime and gefitinib in combination withintravenous and oral irinotecan.
In Aim 2 we will evaluate the mTOR inhibitor CCI-779 as a single agent andrapamycin in combination with cisplatin and irinotecan, defining toxicity, potential activity and surrogatemarkers of tumor response.
In Aim 3 we will evaluate the effect of bevacizumab on tumor vasculature andtumor response in combination with topotecan and with an available mTOR inhibitor using biomarkers andnoninvasive imaging. Lastly, Aim 4 will focus on the evaluation of insulin-like growth factor type -1 receptor(IGF-1 R) inhibitors alone and in combination with an mTOR inhibitor, defining toxicity, pharmacokineticparameters, potential activity and the effects of downregulation of IGF-1 R. This clinical project isfundamental in translating key laboratory discoveries into the treatment approaches for children with solidtumors and providing direction for continued laboratory investigations.
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