Although contemporary treatment strategies have improved the survival of children with solid tumors, relapse or refractory disease still accounts for the leading cause of death in these children. New therapeutic strategies are needed and a further understanding of the biologic and biochemical processes that control tumor proliferation, differentiation and cell death to provide insights into how promising new chemotherapeutic and biologic agents can be incorporated into treatment regimens. This Project 10 comprises the clinical Phase I/II research studies of this Program Project Grant and focuses on 3 hypotheses: (1) that the rapamycin analogue CCI-779 will inhibit the signal transduction molecule mTOR (target of rapamycin) and retard the growth of pediatric tumors; (2) that an inhibitor of ErbB1 signaling (ZD1839) in combination with intravenous camptothecins will produce clinically meaningful responses in children with neuroblastoma and highgrade gliomas either through direct inhibition of ErbB1 in tumors expressing this receptor (glioblastomas) or through modulating ABC transporters such as BCRP and MRP in neuroblastoma; and (3) that 4-anilinoquinazolones such as ZD1839 may modulate the bioavailability of oral camptothecins and result in systemic exposures associated with response in pre-clinical xenograft models. Incorporated into selected clinical trials will be assessments of the expression of the ErbB family of receptors and BCRP/MRP, and mTOR inhibition and recovery. Each clinical trial is derived from observations in laboratory projects.
Specific aim 1 focuses on evaluation of CCI-779 as a single agent or in combination defining toxicity, potential activity and markers of tumor response.
In Specific aims 2 and 3, we will evaluate oral ZD1839 in combination with intravenous or oral camptothecins defining the MTD, bioavailability and tumor responses. Lastly, Specific aim 4 will focus on continued evaluation of a pharmacokinetically targeted approach to dosing of topotecan for relapsed Wilms tumor and combination studies of camptothecins with DNA damaging agents. This clinical project is fundamental in translating key laboratory discoveries into the treatment approaches for children with solid tumors, and providing direction for continued laboratory investigations.
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