INSULIN-LIKE GROWTH FACTOR SIGNALING AS A THERAPEUTIC TARGET IN CHILDHOOD SARCOM

尽管大量文献表明儿童肉瘤细胞利用胰岛素样生长因子(IGF)来 维持自分泌和旁分泌驱动的增殖，阻断与IGF-1类型的配体结合的抗体 胰岛素样生长因子受体(IGF-1R)在临床上已证明是令人失望的。我们的数据显示，IGF-1受体靶向的一个作用 抗体的作用是抑制血管生成和肉瘤细胞增殖。然而，肿瘤分泌的IGF-2，信号 通过胰岛素受体(IN-R)可以避开这些影响。我们将采用候选基因方法进行测试 从IGF/IN的表达预测肿瘤对IGF-1R靶向抗体治疗的敏感性 受体和配体，治疗前或治疗后。我们将采取一种不那么偏见的方法，通过筛选 受体酪氨酸激酶siRNA文库，以识别可能对抗体治疗产生抵抗的受体。在……里面 目的2，我们将寻求通过阻断IGF-1R靶向抗体来增强其抗肿瘤活性的方法 使用配体结合抗体、IGF-1R/IN-R的小分子抑制剂或Akt信号传递IGF-2信号。 初步结果表明，IGF-2通过TOR在两个血管中强有力地激活STATS信号 内皮细胞和肉瘤细胞。此外，STATS与N F-K B进行了交叉谈判，因此，我们将评估 IGF导向的抗体与这些通路的抑制剂的组合，并确定其 在体外和肉瘤移植模型中对血管生成和肿瘤细胞增殖的影响。在《目标3》中，我们将 IGFS拮抗TOR抑制剂诱导的细胞凋亡的机制探讨(S) 肉瘤细胞。我们以前的数据显示，IGF-1通过Akt-1诱导BAD的磷酸化。 体外独立途径和IGF-IR靶向抗体在体外和尤文肉瘤中抑制这种作用 雷帕霉素诱导细胞凋亡的异种移植模型。我们将探索IGF-2如何保护细胞免受 雷帕霉素或TOR激酶抑制剂，并确定IGF-2保护是否通过STATS介导 信号转导，以及这是否可以被阻断IGF-2/IN-R信号转导的抗体或被 统计数据。P项目3与项目2(STATS信令)高度互动，影响N F-K B/S T A T T S的角色 项目1中的信令，严重依赖核心(1-3)。 相关性(请参阅说明)： 胰岛素样生长因子信号在每种被研究的肉瘤组织类型中都是失调的。建议的工作 将阐明胰岛素样生长因子-1受体靶向抗体治疗的内在和获得性耐药的机制(S)，以及 测试可以克服或逆转这种阻力的潜在组合。我们的研究还将确定 IGF保护肉瘤细胞免于凋亡的途径，并研究选择性地 IGF-IR阻断可使血管内皮细胞和肉瘤细胞发生凋亡。

Despite a vast literature showing that childhood sarcoma cells utilize insulin-like growth factors (IGFs) to maintain autocrine and paracrine-driven proliferation, antibodies that block ligand binding to the type IGF-1 receptor (IGF-1 R) have proven disappointing in the clinic. Our data show that one effect of IGF-1 R-targeted antibodies is to inhibit angiogenesis and sarcoma cell proliferation. However, tumor-secreted IGF-2, signaling through the insulin receptor (IN-R) circumvents these effects. We will take a candidate gene approach to test whether tumor sensitivity to IGF-1 R-targeted antibody therapy can be predicted from the expression of IGF/IN receptors and ligands, before treatment or after treatment. We will take a less-biased approach by screening a receptor tyrosine kinase siRNA library to identify receptors that may confer resistance to antibody treatment. In Aim 2, we will pursue approaches to enhance the antitumor activity of IGF-1 R-targeted antibodies by blocking IGF-2 signaling using ligand binding antibodies, small molecule inhibitors of IGF-1 R/IN-R, or Akt signaling. Preliminary results demonstrate that IGF-2 robustly activates STATS signaling via TOR in both vascular endothelial and sarcoma cells. Further, STATS cross-talks with N F - K B , consequently, we will evaluate combinations of IGF-directed antibodies combined with inhibitors of these pathways and determine their effects on angiogenesis and tumor cell proliferation in vitro and in sarcoma xenograft models. In Aim 3, we will explore the mechanism(s) by which IGFs protect against apoptosis induced by TOR inhibitors in some sarcoma cells. Our previous data showed that IGF-1 induces phosphorylation of BAD, through an Akt- independent pathway in vitro, and IGF-IR targeted antibody suppressed this in vitro and in a Ewing sarcoma xenograft model leading to rapamycin-induced apoptosis. We will explore how IGF-2 can protect cells from rapamycin or TOR kinase inhibitors, and determine whether IGF-2 protection is mediated through STATS signaling, and whether this can be inhibited by antibodies that block IGF-2/IN-R signaling or by inhibitors of STATS. pProject 3 is highly interactive with Project 2 (STATS signaling), impacts the role of N F - K B / S T A T S signaling in Project 1 and relies heavily on Cores (1-3). RELEVANCE (See instructions): Insulin-like growth factor signaling is dysregulated in each sarcoma histotype being studied. Work proposed will elucidate the mechanism(s) of intrinsic and acquired resistance to IGF-1 R-targeted antibody therapy, and test potential combinations that will overcome or reverse this resistance. Our studies will also identify pathways by which IGFs protect sarcoma cells from apoptosis, and examine strategies for selectively sensitizing vascular endothelial cells and sarcoma cells to undergo apoptosis in response to IGF-IR block.