Over the past several decades the cure rate for children with cancer has increased, but those children with therapy-resistant disease are still in need of new treatment approaches. One such strategy involves targeting the vasculature upon which tumor growth and spread are dependent. Angiogenesis inhibitors are already being introduced into the clinic for the treatment of children with solid tumors, often in combination with adjuvant therapy including chemotherapeutic drugs and ionizing radiation. However, no rational guidelines exist to assist the clinician in determining the optimal dosing and scheduling for angiogenesis inhibitors, particularly in pediatric patients. The overriding hypothesis of this proposal is that through an improved understanding and monitoring of the phenotypic and functional changes in the tumor vasculature effected by angiogenesis inhibitors, significant improvements in the antitumor efficacy of conventional cytotoxic agents can be achieved for the treatment of children with solid malignancies. We plan to use orthotopic pediatric xenografts to 1) assess the potential of noninvasive imaging modalities to accurately and reliably evaluate changes in the tumor vasculature in response to anti-angiogenic therapy, 2) determine the optimal treatment schedule of therapy that combines anticancer drugs with angiogenesis inhibitors, based on an understanding of the mechanism and timing of tumor vessel response to anti-angiogenic agents, 3) determine the effect that anti-angiogenic agents have on the expression and function of drug export and resistance proteins, and 4) devise a model based on pharmacokinetic and pharmacodynamic data that will predict the optimal use of anti-angiogenic agents for pediatric patients with solid malignancies. The results of our studies have great potential to contribute to the rational use of angiogenesis inhibitors in the treatment of children with solid tumors.
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