Enhancing Treatment Response by Leveraging STAT5-OLIG2 signaling in GBM

利用 GBM 中的 STAT5-OLIG2 信号传导增强治疗反应

基本信息

  • 批准号:
    10263545
  • 负责人:
  • 金额:
    $ 58.02万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-30 至 2021-08-31
  • 项目状态:
    已结题

项目摘要

Project Summary Glioblastoma (GBM) is among the most treatment resistant and lethal of all human cancers. Effective GBM treatment is hindered by aggressive tumor cell invasion into surrounding healthy brain tissue that invariably leads to tumor recurrence. Therefore, the development of therapies that target the infiltrative, residual cells are greatly needed in order to improve the survival of GBM patients. We previously reported that the expression of the TNF receptor superfamily member Fn14 is high in infiltrating glioma cells. Increased Fn14 signaling promotes GBM cell migration/invasion and chemoresistance in vitro while Fn14 depletion increases sensitivity to temozolomide (TMZ) and survival in an intracranial xenograft model. Fn14 is an inducible protein that can be activated by constitutively active receptor tyrosine kinases such as amplified EGFR and its active mutant EGFRvIII. EGFRvIII-induced Fn14 upregulation is mainly driven by STAT5 activity to promote glioma invasion and therapeutic resistance. Notably, both Fn14 expression and STAT5 activation are elevated in GBM patient-derived xenograft (PDX) lines selected for temozolomide (TMZ) resistance. Inhibition of JAK1/2 expression/activity in EGFRvIII expressing GBM cells did not affect the phosphorylation of STAT5 (pSTAT5), which is essential for its activation, or Fn14 expression suggesting that STAT5 activation is independent of JAK1/2. Intriguingly, we find that expression of OLIG2, a key cell fate factor important for the tumorigenic potential of glioma stem cells (GSCs), affects STAT5 activation and Fn14 expression. In GSCs, STAT5 interacts with OLIG2 and treatment with the STAT5 inhibitor, pimozide results in decreased Fn14 expression and invasion of GSCs. The upstream molecular mechanisms involved in JAK-independent activation of STAT5 and downstream signaling pathway(s) regulated by OLIG2-STAT5 complex must be identified to ultimately target invasive GSCs. We hypothesize that the STAT5/OLIG2/Fn14 signaling pathway is a node of vulnerability in the invasive, residual GBM cells and targeting this pathway will decrease therapeutic resistance and increase survival in PDX models. In Aim 1, we will determine the mechanism(s) by which STAT5 signaling induces Fn14 expression downstream of EGFRvIII to enhance GBM cell invasion and therapeutic resistance. Aim 2 will identify the molecular mechanism(s) involved in OLIG2-mediated regulation of STAT5-Fn14 expression in GSCs. In Aim 3 we will determine the impact of STAT5 inhibition in combination with TMZ and IR on GBM tumor growth and therapeutic resistance in intracranial xenografts and syngeneic immunocompetent mouse models of GBM. Success of the proposal will identify, validate, and place into a clinically meaningful context the STAT5/OLIG2/Fn14 signaling pathway as a therapeutic target for infiltrating cells that commonly underlie GBM fatality.
项目摘要 胶质母细胞瘤(GBM)是最具抗药性和致命性的人类癌症之一。有效的GBM 治疗受到侵袭性肿瘤细胞侵袭周围健康脑组织的阻碍 会导致肿瘤复发。因此,针对浸润性残留细胞的治疗方法的发展 都是非常需要的,以提高GBM患者的生存。我们之前曾报道过, 肿瘤坏死因子受体超家族成员Fn14在浸润性胶质瘤细胞中高表达。增加了 Fn14信号在体外促进GBM细胞迁移/侵袭和化疗耐药而Fn14缺失 增加对替莫唑胺(TMZ)的敏感性和在颅内异种移植模型中的存活率。Fn14是一种 可被结构性活性受体酪氨酸激酶激活的可诱导蛋白,如扩增的 EGFR及其活性突变体EGFRvIII。EGFRvIII诱导的Fn14上调主要由STAT5驱动 促进胶质瘤侵袭和治疗耐药的活性。值得注意的是,Fn14表达和STAT5 替莫唑胺(TMZ)选择的GBM患者来源的异种移植(PDX)系中的激活水平升高 抵抗。抑制表达EGFRvIII的GBM细胞中JAK1/2的表达/活性不影响 STAT5(PSTAT5)的磷酸化,这是其激活所必需的,或者Fn14的表达提示 STAT5的激活不依赖于JAK1/2。有趣的是,我们发现关键细胞OLIG2的表达 影响神经胶质瘤干细胞(GSCs)致瘤潜能的命运因素影响STAT5的激活 和Fn14的表达。在GSCs中,STAT5与OLIG2相互作用,并用STAT5抑制剂治疗, Pimozide导致Fn14表达减少,GSCs侵袭力下降。上游分子 JAK非依赖性激活STAT5及其下游信号通路的机制(S) 受OLIG2-STAT5调控,必须确定复合体才能最终靶向侵袭性GSCs。我们 假设STAT5/OLIG2/Fn14信号通路是侵袭性中的一个脆弱性节点, 残留的GBM细胞和靶向该通路将减少治疗耐药性并提高存活率 在PDX型号中。在目标1中,我们将确定STAT5信号诱导Fn14的机制(S 在EGFRvIII下游表达可增强GBM细胞侵袭力和治疗耐药性。目标2将 确定OLIG2调节STAT5-Fn14表达的分子机制(S) GSCS。在目标3中,我们将确定STAT5抑制联合TMZ和IR对基底膜的影响 颅内移植瘤生长和治疗耐药与同种免疫活性 小鼠肾小球基底膜模型。该提案的成功将确定、验证并放置在具有临床意义的 背景:STAT5/OLIG2/Fn14信号通路是常见的浸润性细胞癌的治疗靶点 GBM致死的基础。

项目成果

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SHWETAL MEHTA其他文献

SHWETAL MEHTA的其他文献

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{{ truncateString('SHWETAL MEHTA', 18)}}的其他基金

STAT5/OLIG2 regulation of GBM therapeutic resistance and recurrence - Resubmit 3.22
STAT5/OLIG2 对 GBM 治疗耐药和复发的调节 - 重新提交 3.22
  • 批准号:
    10583973
  • 财政年份:
    2023
  • 资助金额:
    $ 58.02万
  • 项目类别:
Downstream Targets of Olig 2
Olig 2 的下游靶标
  • 批准号:
    7488486
  • 财政年份:
    2006
  • 资助金额:
    $ 58.02万
  • 项目类别:
Downstream Targets of Olig 2
Olig 2 的下游靶标
  • 批准号:
    7111895
  • 财政年份:
    2006
  • 资助金额:
    $ 58.02万
  • 项目类别:
Downstream Targets of Olig 2
Olig 2 的下游靶标
  • 批准号:
    7255692
  • 财政年份:
    2006
  • 资助金额:
    $ 58.02万
  • 项目类别:

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