TWIST1 as a target for inhibition of glioma invasion

描述（申请人提供）：胶质母细胞瘤（GBM）是恶性程度最高、最常见的脑肿瘤。尽管进行了积极的治疗，这种疾病仍然是致命的，患者平均存活时间不到一年。我们无法改善疾病的结果，在很大程度上是由于我们对激活GBM侵袭的机制的理解存在差距。我们首次发现TWIST1在GBM侵袭中的作用及其与人类GBM恶性肿瘤的高度相关性。它通过激活上皮间充质转化（epithelial mesenchymal transition， EMT）在癌的侵袭和转移中起关键作用，这表明它可能通过类似的机制促进GBM的侵袭。本研究的新数据表明，分泌基质蛋白POSTN、Akt激活和TWIST1结合蛋白相互作用在GBM中TWIST1促侵袭信号传导中的潜在作用。我们假设TWIST1的调控机制通过POSTN和特异性Akt亚型信号传导，进而由TWIST1结合伙伴调控，促进GBM侵袭和恶性肿瘤。为了验证这一假设，并展示针对TWIST1信号网络的治疗潜力，我们将i)确定在人GBM干细胞和cre/lox条件TWIST模型中，TWIST1的抑制如何影响体内肿瘤侵袭和恶性，ii)确定抑制POSTN和特异性Akt亚型对体内消除TWIST1促侵袭信号的影响。iii)鉴定与POSTN和Akt调控一致调控TWIST1侵袭的TWIST1结合伙伴。通过证明该网络对GBM侵袭的重要性，我们将进一步验证EMT机制在非上皮源性癌症中的相关性。因此，这些研究有望彻底改变GBM侵袭的概念，并加速开发针对这些可怕癌症最致命生物学特征的急需治疗方法。

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.