Truncated NK1R in GBM: Pharmacology and Relationship with Patient Survival

描述（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）均无效，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。其中一个目标是神经激肽1受体（NK1R），这是一种介导p物质作用的G蛋白偶联受体。NK1R以两种剪接形式存在：全长形式，包含407个氨基酸，以及截断形式，结束于氨基酸311。对NK1R在GBM细胞中利用的信号转导途径的描述表明，该受体激活了至少7个靶点（EGFR、IGF-1R、Src、Akt、NF-kB、IL-6和VEGF），这些靶点之前被认为在GBM生长中起关键作用。阻断NK1R可抑制细胞系和GBM干细胞的GBM生长。2009年，我们的实验室有了一个重要的发现：在GBM中，NK1R的一小部分是组成活性的。我们最近的数据表明，这种活性源于NK1R的截断形式。有趣的是，2005年的一项研究表明，在正常乳腺细胞中，NK1R的截断形式的表达，而不是全长形式的表达，会导致表型转化。我们发现截断的NK1R以不同的表达水平存在于我们所测试的每一个原发性GBM肿瘤中。这一观察结果提出了一种可能性，即GBM中截断的NK1R水平可以预测疾病的严重程度，从而预测生存。因此，拟议研究的目的1将检查我们有生存数据的患者的GBM肿瘤中NK1R截短形式的表达。拟议研究的目的2将确定截断的NK1R的药理学是否与全长的NK1R不同。拟议的研究将使我们更接近于在GBM患者中测试基于nk1r的治疗方法。PI在NK1R生物学方面的专业知识和杜克大学Preston Robert Tisch脑肿瘤中心可用资源的独特结合确保了这些研究的成功完成。

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.