MTOR AS A THERAPEUTIC TARGET IN PEDIATRIC SOLID TUMORS

在过去的资助期间，我们的重点是了解雷帕霉素的作用机制， 并在这些mTOR抑制剂的背景下开发合理的组合。这项工作是基于我们的 早期的研究表明，IGF-II/IGF 1 R信号在横纹肌肉瘤中，雷帕霉素有效地 抑制这些细胞的增殖。我们现在已经确定了mTOR下游的一条通路， 存活，并且当用雷帕霉素处理时，p53功能缺陷的细胞经历凋亡。 缺乏外源性IGF-I。选择性阻断IGF-IR信号传导的试剂（抗体和小分子抗体两者） 具有合理的体内药代动力学的分子），并且将是工作的重点 提议： 假设1：在mTOR抑制的背景下靶向IGF-IR通路将是有效的， 代偿途径也被阻断。 目标1.明确IGF-1 R信号在肉瘤和神经母细胞瘤异种移植物中的作用。 假设2：Akt的抑制在抑制肿瘤源性VEGF方面比Akt的抑制更有效。 mTOR抑制，并且IGF-IR途径中的抑制剂的组合将是有效的抗肿瘤和抗肿瘤药物。 抗血管生成治疗 目标2.为了明确IGF-IR/Akt/mTOR信号在VEGF产生和血管生成中的作用， 体外和体内的儿童肿瘤模型。 假设3：基线（未治疗）或药物/抗体治疗后的分子特征 靶向IGF-IR途径将确定肿瘤对治疗的反应性。 目标3.确定预测IGF-IR靶向治疗反应的潜在生物标志物， 表达和蛋白质组学分析。 这些目标的成功完成将确定IGF-I受体作为治疗靶点的相关性， 不存在mTOR抑制，并可能鉴定肿瘤特异性变化， 作为潜在的另外的治疗靶点补偿IGF-IR抑制。总体目标是测试 在适当的异种移植模型中的治疗策略，并使用结果设计临床方案。

Over the last period of funding our focus has been to understand the mechanism of action of rapamycins, and develop rational combinations in the context of these mTOR inhibitors. This work was based on our earlier studies demonstrating IGF-II/IGF1R signaling in rhabdomyosarcomas, and that rapamycin potently inhibited proliferation of these cells. We have now identified a pathway downstream of mTOR that signals survival, and that cells defective in p53 function undergo apoptosis when treated with rapamycin in the absence of exogenous IGF-I. Reagents that selectively block IGF-IR signaling (both antibodies and small molecules with reasonable in vivo pharmacokinetics) are now available, and will be the focus of the work proposed: Hypothesis 1: Targeting the IGF-IR pathway in the context of mTOR inhibition will be effective if compensatory pathways are also blocked. Aim 1. To define the role of IGF-IR signaling in sarcoma and neuroblastoma xenografts. Hypothesis 2: That inhibition of Akt will be more effective in suppressing tumor-derived VEGF than mTOR inhibition, and that the combination of inhibitors in the IGF-IR pathway will be effective antitumor and antiangiogenic therapy. Aim 2. To define the role of IGF-IR/Akt/mTOR signaling in VEGF production and angiogenesis in models of childhood tumors in vitro and in vivo. Hypothesis 3: That molecular signatures at baseline (untreated) or post treatment with drugs/antibodies targeting the IGF-IR pathway will define tumor responsiveness to treatment. Aim 3. To define potential biomarkers that predict response to IGF-IR-directed therapies using expression and proteomics profiling. Successful completion of the aims will define the relevance of the IGF-I receptor as a therapeutic target, in the absence of presence of mTOR inhibition, and potentially identify tumor-specific changes that compensate for IGF-IR inhibition as potential additional therapeutic targets. The overall objective is to test therapeutic strategies in appropriate xenograft models, and use the results for design of clinical protocols.