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

胰岛素样生长因子信号作为儿童肉瘤的治疗靶点

• 批准号: 8745056
• 负责人: PETER J HOUGHTON
• 金额: $ 26.1万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8745056
• 关键词: Accounting; Aftercare; Angiogenesis Inhibitors; Antibodies; Antibody Therapy; Apoptosis; Blocking Antibodies; Blood Vessels; Candidate Disease Gene; Cell Proliferation; Cell Survival; Cells; Cellular Stress; Childhood; Clinic; Cytostatics; Data; Ewings sarcoma; In Vitro; Instruction; Insulin Receptor; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Insulin-Like-Growth Factor I Receptor; Libraries; Ligand Binding; Ligands; Literature; Malignant Childhood Neoplasm; Mediating; Modeling; Pathway interactions; Phosphorylation; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Resistance; Rhabdomyosarcoma; Role; Signal Pathway; Signal Transduction; Sirolimus; Small Interfering RNA; Somatomedins; Testing; Tumor-Derived; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Work; Xenograft Model; Xenograft procedure; angiogenesis; antiangiogenesis therapy; autocrine; inhibiting antibody; inhibitor/antagonist; kinase inhibitor; migration; neoplastic cell; osteosarcoma; paracrine; preclinical study; receptor; response; sarcoma; screening; small molecule; therapeutic target; tumor; tumor growth

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.

尽管大量文献显示儿童肉瘤细胞利用胰岛素样生长因子（IGFs）， 维持自分泌和旁分泌驱动的增殖，阻断配体与IGF-1型结合的抗体 胰岛素样生长因子受体（IGF-1 R）的作用在临床上已被证明是令人失望的。我们的数据表明，IGF-1 R靶向的一种作用是， 抗体是抑制血管生成和肉瘤细胞增殖。然而，肿瘤分泌的IGF-2， 通过胰岛素受体（IN-R）来避免这些作用。我们将采取候选基因的方法来测试 肿瘤对IGF-1 R靶向抗体治疗的敏感性是否可以从IGF/IN的表达预测 受体和配体，治疗前或治疗后。我们将采取较少偏见的方法， 受体酪氨酸激酶siRNA文库，以鉴定可赋予抗体治疗抗性的受体。在 目的2：通过阻断IGF-1受体的表达，增强IGF-1受体靶向抗体的抗肿瘤活性 使用配体结合抗体、IGF-1 R/IN-R的小分子抑制剂或Akt信号传导的IGF-2信号传导。 初步结果表明，IGF-2通过TOR在两种血管中强烈激活STATS信号传导， 内皮细胞和肉瘤细胞。此外，STATS与NF- K B的串扰，因此，我们将评估 IGF-定向抗体与这些途径的抑制剂的组合，并确定它们的 在体外和肉瘤异种移植模型中对血管生成和肿瘤细胞增殖的作用。在目标3中，我们 探索IGFs在某些细胞中保护TOR抑制剂诱导的细胞凋亡的机制。 肉瘤细胞我们以前的数据表明，IGF-1通过Akt-1诱导BAD磷酸化， IGF-IR靶向抗体在体外和尤文肉瘤中抑制了这一点 异种移植模型导致雷帕霉素诱导的细胞凋亡。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 信号传导，以及这是否可以通过阻断IGF-2/IN-R信号传导的抗体或通过IGF-2/IN-R信号传导的抑制剂来抑制。 STATS. pProject 3与Project 2（STATS信号）高度交互，影响NF- K B / S T A T S的作用 项目1中的信令并且严重依赖于核心（1-3）。 相关性（参见说明）： 胰岛素样生长因子信号在每种研究的肉瘤组织型中均失调。工作提出的 将阐明对IGF-1 R靶向抗体治疗的内在和获得性抗性的机制， 测试能够克服或逆转这种阻力的潜在组合。我们的研究还将确定 IGFs保护肉瘤细胞免于凋亡的途径，并研究选择性地 使血管内皮细胞和肉瘤细胞敏感，以响应IGF-IR阻断而经历凋亡。