Regression of meningioma tumor growth by combination therapy

通过联合疗法消退脑膜瘤肿瘤生长

基本信息

批准号：
7435980
负责人：
JASTI S. RAO
金额：
$ 34.34万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-15 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7435980
关键词：
Adhesions Adverse effects Anaplastic Meningioma Antisense Oligonucleotides Apoptosis Apoptotic Arachnoid Membrane Basement membrane Behavior Benign Benign Meningiomas Binding Brain Neoplasms Cathepsins B Cell Death Cell Line Cell Proliferation Cerebrum Characteristics Coke Combined Modality Therapy Development Diagnosis Disease regression Endopeptidases Enzymes Extracellular Matrix Gelatinase B Genes Green Fluorescent Proteins Growth Human Immune response In Vitro Intracranial Neoplasms Invaded Invasive Leptomeninges Location Maintenance Malignant - descriptor Malignant Neoplasms Matrix Metalloproteinases Membrane Proteins Messenger RNA Modality Molecular Neoplasm Metastasis Nude Mice Numbers Oligonucleotides Operative Surgical Procedures Pathogenesis Pathway interactions Patients Peptide Hydrolases Process Protein Overexpression Public Health RNA Interference Radiation Radiation therapy Radiosurgery Recurrence Residual state Resistance Risk Small Interfering RNA Specificity Survivors Therapeutic Therapeutic Effect Therapeutic Intervention Treatment outcome Tumor Cell Invasion angiogenesis base brain tissue cancer cell cancer therapy cell growth dosage improved in vivo insight irradiation malignant phenotype meningioma migration neoplastic cell novel novel therapeutics tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Regression of meningioma tumor growth by combination therapy Fifteen percent of meningiomas have malignant characteristics and these aggressive invasive tumors are frequently fatal. Radiotherapy remains a major component of treatment modalities for controlling both malignant and benign meningiomas. In patients with residual or recurring benign tumors, there is increasing concern about radiation- related side effects that may occur even with highly accurate therapies such as radiosurgery. Besides therapeutic effect, recent evidence has shown that irradiation may promote malignant behaviors of cancer cells both in vitro and in vivo by activating several pathways involved in tumor invasiveness, angiogenesis and metastasis. Several studies, including ours, demonstrated significantly increased levels of uPA, uPAR, MMP- 9, and cathepsin B in malignant meningiomas. To determine the molecular interactions between radiation and uPA, uPAR, MMP-9, and cathepsin B in meningiomas, we propose the following specific aims: Specific Aim 1: Determine the effect of various siRNA bicistronic constructs combined with irradiation on meningioma cell growth, attachment, apoptosis, migration, and invasion in vitro. Aim 1a: Determine the effect of various siRNA bicistronic constructs combined with irradiation on the levels of uPA, uPAR, MMP-9 and cathepsin B in meningioma cell lines. Aim 1b: Evaluate the effect of various siRNA bicistronic constructs combined with irradiation on the molecular mechanisms of proliferation in meningioma cell lines. Aim 1c: Investigate the effect of various siRNA bicistronic constructs combined with irradiation on the molecular mechanisms of apoptosis in meningioma cell lines. Aim 1d: Determine the effect of various siRNA bicistronic constructs combined with irradiation on adhesion, migration and invasion in meningioma cell lines. Specific Aim 2: Evaluate the effect of various bicistronic siRNA constructs combined with irradiation treatment on meningioma tumor growth and angiogenesis in nude mice. Aim 2a: Determine the optimal dosage of various bicistronic siRNA constructs in the absence of irradiation for inhibition of pre- established intracranial tumor growth or invasiveness of human meningioma cell lines injected intracerebrally in nude mice. Aim 2b: Determine the effect of various bicistronic siRNA constructs combined with irradiation of pre-established intracranial tumor growth in nude mice. Aim 2c: Evaluate the effect of various bicistronic siRNA constructs alone or in combination with irradiation on cerebral angiogenesis in both in vitro and in vivo. The proposed studies should generate major insights into the pathogenesis of radiation-induced alterations in tumors and, in turn, should suggest novel targets for therapeutic interventions of meningiomas. PUBLIC HEALTH RELEVANCE: Fifteen percent of meningiomas have malignant characteristics and these aggressive, invasive tumors are frequently fatal. Radiotherapy remains a major component of treatment modalities for controlling both malignant and benign meningiomas. However, an increasing number of long survivors with secondary side effects from this treatment highlighted the need for development of novel therapeutic approaches. This proposal represents a combinational therapeutic approach using bicistronic siRNA. This strategy may improve radiotherapy outcomes for the treatment of meningiomas.

描述（由申请人提供）：组合治疗的脑膜瘤肿瘤生长的回归15％的脑膜瘤具有恶性特征，而这些侵略性的浸润性肿瘤经常致命。放射疗法仍然是控制恶性和良性脑膜瘤的治疗方式的主要组成部分。在残留或经常性良性肿瘤的患者中，即使使用诸如放射外科手术之类的高度精确疗法，也可能会出现辐射相关的副作用。除了治疗作用外，最近的证据表明，辐射可以通过激活参与肿瘤侵袭性，血管生成和转移的几种途径来促进癌细胞的恶性行为。包括我们的几项研究，包括恶性脑膜瘤中的UPA，UPAR，MMP-9和组织蛋白酶B的水平显着升高。为了确定辐射和UPA，UPAR，MMP-9和脑膜炎中的组织蛋白酶B之间的分子相互作用，我们提出以下特定目标：具体目标1：确定各种siRNA双sistronic构建体与辐照对脑膜瘤细胞生长的影响，，体外凋亡，迁移和侵袭。 AIM 1A：确定各种siRNA双分裂构建体的影响以及辐照对脑膜瘤细胞系中UPA，UPAR，MMP-9和组织蛋白酶B水平的影响。 AIM 1B：评估各种siRNA双散发器构建体的作用，以及辐照对脑膜瘤细胞系增殖的分子机制的结合。 AIM 1C：研究各种siRNA双分裂构建体的影响，结合辐射对脑膜瘤细胞系中凋亡的分子机制。 AIM 1D：确定各种siRNA双分裂构建体的影响以及辐照对脑膜瘤细胞系的粘附，迁移和侵袭的影响。具体目的2：评估各种双科siRNA构建体以及辐照处理对裸鼠脑膜瘤肿瘤生长和血管生成的影响。 AIM 2A：在没有辐照的情况下，确定各种双科siRNA构建体的最佳剂量，以抑制预先确定的颅内肿瘤生长或人脑膜瘤细胞系在裸鼠中注射脑内脑内脑膜细胞系的侵入性。 AIM 2B：确定各种双分散性siRNA构建体的作用，并结合裸鼠的颅内肿瘤生长的辐射。 AIM 2C：单独评估单独或与辐照对体外和体内脑血管生成的影响。拟议的研究应产生对辐射诱导的肿瘤改变的发病机理的重大见解，进而提出了脑膜瘤治疗干预措施的新靶标。公共卫生相关性：15％的脑膜瘤具有恶性特征，这些侵略性的侵入性肿瘤经常致命。放射疗法仍然是控制恶性和良性脑膜瘤的治疗方式的主要组成部分。但是，越来越多的长期幸存者具有这种治疗方法的继发性副作用，这突显了开发新型治疗方法的需求。该提案代表了使用Bicistronic siRNA的组合治疗方法。该策略可以改善放射治疗的脑膜瘤治疗结果。