Chemoprevention of Gliomas using Nitrones with Anti-c-Met Activity

使用具有抗 c-Met 活性的硝酮化学预防神经胶质瘤

• 批准号: 7474147
• 负责人: Rheal A Towner
• 金额: $ 7.75万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7474147
• 关键词: Angiography; Apoptosis; Behavior; Binding; Biology; Blood - brain barrier anatomy; Blood flow; Brain; Brain Neoplasms; Cancer Model; Cell Proliferation; Cells; Characteristics; Chemoprevention; Clone Cells; Data; Detection; Development; Diagnosis; Diagnostic; Effectiveness; Fluorescence; Gadolinium; Glioblastoma; Glioma; Growth; Hepatocyte Growth Factor; Histology; Human; Image; Imaging Techniques; Immunofluorescence Immunologic; Immunohistochemistry; Intervention; Invasive; Link; Magnetic Resonance; Magnetic Resonance Angiography; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Mediator of activation protein; Methodology; Methods; Modeling; Molecular Biology; Molecular Target; Morphology; Nature; Neoplasms in Vascular Tissue; Normal Cell; Numbers; Operative Surgical Procedures; Other Therapy; Patients; Play; Primary carcinoma of the liver cells; Principal Investigator; Process; Publishing; Rattus; Receptor Protein-Tyrosine Kinases; Rodent; Rodent Model; Role; SU 11657; Small Interfering RNA; Techniques; Therapeutic Agents; Thinking; Time; Vascularization; Western Blotting; albumin-(gadolinium-DTPA); angiogenesis; antitumor agent; experience; implantation; improved; in vivo; inhibitor/antagonist; nitrone; novel; outcome forecast; prevent; tumor; tumor growth; tumor progression; tumorigenic

DESCRIPTION (provided by applicant): This project is focused on establishing the mechanism of alpha-phenyl-tert-butyl nitrone (PBN), in its ability to inhibit glioma formation in experimental rodent models that vary in tumor grade. We have promising preliminary data that clearly demonstrates that PBN can potentially be an effective anti-tumor agent in vivo, prior to tumor implantation, or once a tumor has formed. Our hypothesis is that c-Met, a tyrosine kinase receptor for the hepatocyte growth factor (scatter factor) plays an integral role in the formation of malignant gliomas, and that altered c-Met levels from PBN treatment suppresses glioma formation. Important hallmarks of malignant gliomas include their invasive behavior and angiogenesis. c-Met is thought to be a mediator in many of the processes of malignant brain tumor progression, including cell proliferation, cell invasion, apoptosis and angiogenesis. Approximately 15,000 patients in the U.S.A. die with glioblastomas per year. Due to the infiltrative nature of gliomas, surgery is rarely effective. Despite modern diagnostics and treatments the median survival time for patients with glioblastomas does not exceed 15 months. A potential chemo-preventative agent that can suppress glioma growth or even eradicate gliomas entirely would be of tremendous benefit to patients that develop malignant tumors. In vivo magnetic resonance (MR) methods are ideally suited to follow changes in tumor growth, angiogenesis, as well as the assessment of c- Met levels which can be used as a marker for predicting the prognosis of gliomas. We currently use non-invasive in vivo MR imaging (MRI) methods to detect tumor morphology, tumor vasculature or angiogenesis (using MR angiography (MRA)), and have preliminary data on c-Met expression (using molecular-targeted MRI). In addition we use molecular biology methods (Western blots, immunofluorescence histology) and histological tumor grading, to correlate with MR imaging, angiography and molecular targeted data. This project will assess PBN in its ability to prevent malignant glioma formation and development, use c-Met knockdown glioma cell clones, and incorporate novel in vivo molecular-targeted MRI techniques for in vivo detection of c-Met in intracranial rat gliomas varying in tumor grades. Intracerebral implantation of rat C6 (forming grade II or III tumors) or RG2 (forming more aggressive grade III or IV tumors) glioma cells will be used in Fisher 344 rats as the glioma models. Specific aim 1 will be to assess the levels of c-Met in the 2 glioma models (C6 and RG2); specific aim 2 will be to establish the effectiveness of PBN as a c-Met suppressor in preventing glioma growth and formation, and to use c-Met knockdown glioma models to further elucidate the role of c-Met in glioma formation; and specific aim 3 will be to develop and validate improved MRI methods for in vivo detection of c-Met expression. There are very few existing agents that are currently applicable for the intervention of malignant gliomas. Other promising characteristics of PBN, in addition to c-Met suppression, are that it is orally bio-available, and it is able to cross the blood-brain-barrier (BBB). PBN seems to be a promising candidate in its ability to be an effective agent against glioma formation, and may be useful as a chemo-preventative agent against glioblastoma multiforme in humans. We have preliminary data that PBN (alpha-phenyl-tert-butyl nitrone) seems to be a promising candidate in its ability to be an effective agent against glioma formation, and may be useful as a chemo-preventative agent against glioblastoma multiforme in humans. Our hypothesis is that c-Met, a tyrosine kinase receptor, plays an integral role in the formation of malignant gliomas, and that PBN is able to decrease c-Met levels, resulting in the suppression of glioma formation. This project will assess PBN in its ability to prevent malignant glioma formation and development, use c-Met knockdown glioma cell clones to elucidate the role of c-Met, and incorporate novel in vivo moleculartargeted MRI (magnetic resonance imaging) techniques for in vivo detection of c-Met in intracranial rat gliomas varying in tumor grades.

描述（由申请人提供）： 该项目的重点是建立α-苯基 - 二丁基硝酸（PBN）的机制，其能力在肿瘤级变化的实验啮齿动物模型中抑制神经胶质瘤的形成。我们拥有有希望的初步数据，这些数据清楚地表明，PBN可能在肿瘤植入之前或肿瘤形成之前可能是体内有效的抗肿瘤剂。我们的假设是，用于肝细胞生长因子（散点因子）的酪氨酸激酶受体C-MET在恶性神经胶质瘤的形成中起着不可或缺的作用，并且从PBN治疗中改变了C-MET水平抑制了胶质瘤的形成。恶性神经胶质瘤的重要标志包括它们的侵入性行为和血管生成。在恶性脑肿瘤进展的许多过程中，C-MET被认为是一种介体，包括细胞增殖，细胞侵袭，凋亡和血管生成。美国约有15,000名患者每年死于胶质母细胞瘤。由于神经胶质瘤的浸润性，手术很少有效。尽管现代诊断和治疗，但胶质母细胞瘤患者的中位生存时间不超过15个月。一种可以完全抑制神经胶质瘤生长甚至完全消除神经胶质瘤的潜在化学预防剂对发展恶性肿瘤的患者具有巨大的好处。体内磁共振（MR）方法非常适合遵循肿瘤生长的变化，血管生成以及C-MET水平的评估，该水平可用作预测神经胶质瘤预后的标志物。目前，我们使用非侵入性体内MR成像（MRI）方法来检测肿瘤形态，肿瘤脉管系统或血管生成（使用MR血管造影（MRA）），并具有C-MET表达的初步数据（使用分子靶向的MRI）。此外，我们使用分子生物学方法（蛋白质印迹，免疫荧光组织学）和组织学肿瘤分级，与MR成像，血管造影和分子靶向数据相关。该项目将评估PBN预防恶性神经胶质瘤形成和发育，使用C-MET敲低胶质瘤细胞克隆的能力，并融合了新型的体内分子靶向MRI技术，以在肿瘤梯度改变颅内大鼠胶质瘤的体内检测C-MET。大鼠C6（形成II级或III级肿瘤）或RG2（形成更具侵略性的III级或IV级肿瘤）的脑内植入膜细胞将用于Fisher 344大鼠作为神经胶质瘤模型。具体目的1将是评估两种神经胶质瘤模型中的C-MET水平（C6和RG2）；具体目标2将是确定PBN作为C-MET抑制器在防止神经胶质瘤生长和形成方面的有效性，并使用C-Met敲低神经瘤模型进一步阐明C-MET在神经胶质瘤形成中的作用；具体目标3将是开发和验证改进的MRI方法，以在体内检测C-MET表达。目前很少有现有代理适用于恶性神经胶质瘤的干预。除C-MET抑制外，PBN的其他有希望的特征是它是口服生物可用的，并且能够越过血脑屏障（BBB）。 PBN似乎是其具有有效药物反对神经胶质瘤的有效药物的能力，并且可以作为对人类中多形胶质母细胞瘤的化学鉴定剂的有效药物的能力。我们有初步的数据，即PBN（α-苯基 - 丁基硝基硝基）似乎是具有有效抗神经胶质瘤形成的有效剂的能力，并且可以作为对人类对胶质母细胞瘤的化学预防剂的有效剂的能力。我们的假设是，酪氨酸激酶受体C-MET在恶性神经胶质瘤的形成中起着不可或缺的作用，并且PBN能够降低C-MET水平，从而抑制神经胶质瘤的形成。该项目将评估PBN预防恶性神经胶质瘤形成和发育的能力，使用C-MET敲低胶质瘤细胞克隆来阐明C-MET的作用，并在体内分子中纳入新颖的MRI（磁共振成像）技术，以在体内检测到内骨内gliomamas gliomas glioras vares的体内检测。