ANGIOGENESIS INHIBITORS IN THE MULTIMODAL TREATMENT OF PEDIATRIC SOLID TUMORS

在过去的几十年里，患有癌症的儿童的治愈率有所提高，但那些患有癌症的儿童 耐药疾病仍然需要新的治疗方法。一种这样的战略涉及到瞄准 肿瘤生长和扩散所依赖的血管系统。血管生成抑制剂已经是 被引入临床用于治疗患有实体肿瘤的儿童，通常与 辅助治疗包括化疗药物和电离辐射。然而，没有合理的指导方针 以帮助临床医生确定血管生成抑制剂的最佳剂量和时间安排， 尤其是在儿科患者中。这一提议的压倒一切的假设是，通过改进 对肿瘤血管的表型和功能变化的理解和监测 血管生成抑制剂--对传统细胞毒剂抗肿瘤效果的显著改善 可达到治疗儿童实体恶性肿瘤的目的。我们计划使用正位儿科 异种移植物1)评估非侵入性成像方式的潜力，以准确和可靠地评估 抗血管生成治疗对肿瘤血管系统的影响：2)确定最佳治疗方案 根据一项理解，将抗癌药物与血管生成抑制剂相结合的治疗方案 肿瘤血管对抗血管生成药物反应的机制和时间，3)决定其效果 抗血管生成药物对药物输出蛋白和耐药蛋白的表达和功能的影响 4)设计一个基于药代动力学和药效学数据的模型，以预测最佳使用 儿童实体肿瘤患者的抗血管生成药物。我们的研究结果有很大的进步 有助于合理使用血管生成抑制剂治疗儿童实体瘤的潜力 肿瘤。

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.