MTOR AS A THERAPEUTIC TARGET IN PEDIATRIC SOLID TUMORS

在上一期的资助中，我们的重点一直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/IGF1R信号在横纹肌肉瘤中的作用，以及雷帕霉素有效 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 在雷帕霉素作用下，P53功能缺陷的细胞发生了凋亡 缺少外源性IGF-I。选择性阻断IGF-IR信号的试剂(抗体和小分子 具有合理体内药代动力学的分子)现已问世，并将成为工作的重点 建议： 假设1：在mTOR抑制的情况下，靶向IGF-IR途径将是有效的，如果 补偿途径也被堵塞。 目的1.明确IGF-IR信号在肉瘤和神经母细胞瘤异种移植中的作用。 假设2：抑制Akt比抑制肿瘤衍生的血管内皮生长因子更有效 MTOR抑制，IGF-IR途径中的抑制剂组合将有效地抗肿瘤和 抗血管生成治疗。 目的2.明确胰岛素样生长因子-IR/Akt/mTOR信号在血管内皮生长因子生成和血管生成中的作用。 体外和体内儿童肿瘤模型的建立。 假设3：药物/抗体治疗前(未治疗)或治疗后的分子特征 以IGF-IR通路为靶点将定义肿瘤对治疗的反应性。 目的3.确定预测胰岛素样生长因子-IR导向治疗反应的潜在生物标志物 表达和蛋白质组学图谱。 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 没有mTOR抑制的存在，并可能识别肿瘤特异性变化， 补偿IGF-IR抑制作为潜在的额外治疗靶点。总体目标是测试 在适当的异种移植模型中的治疗策略，并使用结果来设计临床方案。

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.