TWIST1 as a target for inhibition of glioma invasion

描述（由申请人提供）：胶质母细胞瘤（GBM）是最恶性和最常见的内源性脑肿瘤。尽管进行了积极的治疗，这种疾病仍然是致命的，患者平均存活不到一年。我们无法改善疾病的结果在很大程度上是由于我们的差距，在什么机制激活GBM入侵的理解。我们首先确定了TWIST 1在GBM侵袭中的作用及其与人类GBM恶性肿瘤的高度相关性。它通过激活上皮间质转化（EMT）在肿瘤侵袭和转移中起关键作用，提示它可能通过类似的机制促进GBM侵袭。在这里，我们提出了新的数据，证明了分泌的基质蛋白POST 1，Akt激活和TWIST 1结合蛋白的相互作用在GBM中的TWIST 1促侵入信号的潜在作用。我们推测TWIST 1的调节机制通过POST 1和特定的Akt亚型信号传导，而这些亚型又由TWIST 1结合伴侣调节，从而促进GBM侵袭和恶性。为了解决这一假设并显示靶向该TWIST 1信号传导网络的治疗潜力，我们将i）确定在人GBM干细胞中和在cre/lox条件性TWIST模型中TWIST 1的抑制如何影响体内肿瘤侵袭和恶性，ii）定义抑制P019和特异性Akt同种型以消除体内TWIST 1促侵袭信号传导的影响，和iii）鉴定与调节POSTs和Akt一致地调节TWIST 1侵入的TWIST 1结合配偶体。通过证明该网络对GBM侵袭的重要性，我们将进一步验证EMT机制在非上皮来源的癌症中的相关性。因此，这些研究有望彻底改变GBM侵袭的概念，并加速产生急需的治疗方法，这些治疗方法针对这些可怕癌症的最致命的生物学特征。 公共卫生相关性：30多年来，胶质母细胞瘤（GBM）患者的治疗结果缺乏显著改善，这主要是由于我们未能解决GBM细胞侵入大脑的问题。TWIST 1是一个公认的癌基因，通过激活上皮间质转化（EMT）促进癌的侵袭和转移。我们现在已经证实了TWIST 1作为GBM侵袭和恶性肿瘤的关键介质，并且在此将首次建立TWIST 1信号网络通过POR 4和Akt的治疗相关性，而POR 4和Akt又由TWIST 1结合伴侣调节。通过证明这种新的促侵袭网络在GBM侵袭中的影响，我们将验证EMT相关机制对GBM的重要性，也预期对更大的侵袭性癌组具有很大的相关性。这种范式转变有望彻底改变我们对GBM侵袭的理解，加速发现治疗靶点，并转化为GBM患者结局的显著改善。

DESCRIPTION (provided by applicant): Glioblastomas (GBM) are the most malignant and common intrinsic brain tumor. Despite aggressive treatment the disease is uniformly fatal and patients survive on average less than a year. Our inability to improve disease outcome is due in large part to gaps in our understanding of what mechanisms activate GBM invasion. We first identified the role of TWIST1 in GBM invasion and its high correlation with human GBM malignancy. Its critical function in carcinoma invasion and metastasis by activation of epithelial mesenchymal transition (EMT) suggested that it may function through similar mechanisms to promote GBM invasion. Here we present novel data demonstrating the potential role of the secreted matrix protein POSTN, Akt activation and TWIST1 binding protein interactions in TWIST1 pro-invasive signaling in GBM. We hypothesize that a TWIST1 regulatory mechanism signaling through POSTN and specific Akt isoforms that is in turn regulated by TWIST1 binding partners promotes GBM invasion and malignancy. To address this hypothesis and show the therapeutic potential of targeting this TWIST1 signaling network we will i) determine how inhibition of TWIST1 in human GBM stem cells and in a cre/lox conditional TWIST model influences tumor invasion and malignancy in vivo, ii) define the impact of inhibiting POSTN and specific Akt isoforms to abrogate TWIST1 pro-invasive signaling in vivo, and iii) identify TWIST1 binding partners that regulate TWIST1 invasion in concert with regulation of POSTN and Akt. By demonstrating the importance of this network for GBM invasion we will further validate the relevance of EMT mechanisms in non-epithelial derived cancers. As such, these studies are expected to revolutionize concepts of GBM invasion and accelerate generation of sorely needed therapies that target the most lethal biological feature of these dreaded cancers. PUBLIC HEALTH RELEVANCE: The lack of significant improvement in treatment outcomes for patients with glioblastoma (GBM) for over 30 years is due largely to our failure to address the problem of GBM cell invasion into the brain. TWIST1 is a putative oncogene which promotes carcinoma invasion and metastasis through activation of epithelial mesenchymal transition (EMT). We have now confirmed TWIST1 as a critical mediator of GBM invasion and malignancy and here will establish for the first time the therapeutic relevance of a TWIST1 signaling network through POSTN and Akt, in turn regulated by TWIST1 binding partners. By demonstrating the impact of this novel pro-invasive network in GBM invasion we will validate the importance of EMT related mechanisms for GBM, also expected to have great relevance for a much larger group of invasive carcinomas. This paradigm shift is expected to revolutionize our understanding of invasion in GBM, accelerate discovery of therapeutic targets, and translate into significant improvements in GBM patient outcomes.