Truncated NK1R in GBM: Pharmacology and Relationship with Patient Survival

描述（由申请人提供）：多形性胶质母细胞瘤（GBM）是成人中最具侵袭性和最常见的原发性脑肿瘤之一。GBM患者预后极差。目前胶质母细胞瘤的治疗方法（包括手术、放疗和化疗）都不有效，中位生存期仅为15个月。研究人员正在寻求更全面地了解胶质母细胞瘤生物学，以确定阻断GBM肿瘤生长的新分子靶点。一种这样的靶标是神经激肽1受体（NK 1 R），其是介导物质P的作用的G蛋白偶联受体。NK 1 R以两种剪接形式存在：全长形式，其具有407个氨基酸，和截短形式，其终止于氨基酸311。对GBM细胞中NK 1 R所利用的信号转导途径的描述表明，该受体激活至少七种先前被鉴定为在GBM生长中起关键作用的靶点（EGFR、IGF-1 R、Src、Akt、NF-kB、IL-6和VEGF）。阻断NK 1 R抑制细胞系以及GBM干细胞中的GBM生长。在2009年，我们的实验室取得了一项关键发现：GBM中的一小部分NK 1 R是组成型活性的。我们最近的数据表明，这种活性源于NK 1 R的截短形式。有趣的是，2005年的一项研究表明，在正常乳腺细胞中，NK 1 R的截短形式而不是全长形式的表达导致转化的表型。我们已经发现，截短的NK 1 R存在于我们测试的每个原发性GBM肿瘤中，具有不同的表达水平。这一观察结果提出了GBM中截短的NK 1 R水平可以预测疾病严重程度并因此预测生存的可能性。因此，拟议研究的目的1将检查我们有生存数据的患者GBM肿瘤中NK 1 R截短形式的表达。拟议研究的目的2将确定截短NK 1 R的药理学是否与全长NK 1 R不同。拟议的研究将使我们更接近于在GBM患者中测试基于NK 1 R的疗法。PI在NK 1 R生物学方面的专业知识和杜克普雷斯顿罗伯特蒂施脑肿瘤中心的资源的独特组合确保了这些研究的成功完成。 公共卫生相关性：多形性胶质母细胞瘤（GBM）是一种致命的脑肿瘤，诊断为GBM的患者在2年内死亡。目前胶质母细胞瘤的治疗方法包括手术、放疗和化疗，但这些方法都是无效的，我们需要开发新的方法来阻止胶质母细胞瘤的生长。我们的实验室已经表明，NK 1 R是抑制GBM生长的良好靶点，并且所提出的研究将确定NK 1 R的截短形式的药理学以及其在GBM肿瘤中的表达是否预测患者存活。

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is among the most aggressive and frequent primary brain tumors in adults. Patients with GBM have an extremely poor prognosis. None of the current treatments for glioblastomas (including surgery, radiation therapy, and chemotherapy) are effective, and median survival is only 15 months. Researchers are seeking to understand glioblastoma biology more fully in order to identify novel molecular targets for blocking GBM tumor growth. One such target is the neurokinin 1 receptor (NK1R), a G protein-coupled receptor that mediates the effects of substance P. NK1R exits in two spliced forms: the full- length form, which has 407 amino acids, and the truncated form, which ends at amino acid 311. Delineation of signal transduction pathways utilized by NK1R in GBM cells indicates that this receptor activates at least seven targets (EGFR, IGF-1R, Src, Akt, NF-kB, IL-6, and VEGF) previously identified as playing key roles in GBM growth. Blockade of NK1R inhibits GBM growth in cell lines as well as in GBM stem cells. In 2009, our laboratory made a key discovery: a fraction of the NK1R in GBM is constitutively active. Our recent data indicate that this activity arises from the truncated form of NK1R. Intriguingly, a 2005 study showed that the expression of the truncated form of NK1R, but not of the full-length form, in normal breast cells results in a transformed phenotype. We have found that the truncated NK1R is present, with varying levels of expression, in every primary GBM tumor that we have tested. This observation raises the possibility that the levels of truncated NK1R in GBM may predict disease severity and hence survival. Therefore, aim 1 of the proposed studies will examine the expression of the truncated form of NK1R in GBM tumors from patients for whom we have survival data. Aim 2 of the proposed study will determine whether the pharmacology of truncated NK1R differs from that of full-length NK1R. The proposed studies will bring us one step closer to testing NK1R-based therapies in GBM patients. The unique combination of the PI's expertise in NK1R biology and the resources available at Duke's Preston Robert Tisch Brain Tumor Center ensures successful completion of these studies. PUBLIC HEALTH RELEVANCE: Glioblastoma multiforme (GBM) is a deadly brain tumor and patients diagnosed with GBM die within 2 years. Current treatments for glioblastomas include surgery, radiation therapy, and chemotherapy, but these are ineffective and we need to develop new ways to block GBM growth. Our laboratory has shown that NK1R is a good target to inhibit the growth of GBM and the proposed studies will determine the pharmacology of the truncated form of NK1R and whether its expression in GBM tumor predicts patient survival.