Combination therapy to inhibit glioma growth by Ad MMP2 and radiation

Ad MMP2 和放射治疗抑制神经胶质瘤生长的联合疗法

• 批准号: 8313963
• 负责人: JASTI S. RAO
• 金额: $ 33.66万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8313963
• 关键词: Adhesions; Adverse effects; Anaplastic Meningioma; Antisense Oligonucleotides; Apoptosis; Apoptotic; Basement membrane; Behavior; Benign; Benign Meningiomas; Brain Neoplasms; Cell Death; Cell Line; Cell Proliferation; Cerebrum; Combined Modality Therapy; Data; Development; Dose; Enzymes; Extracellular Matrix Degradation; Gelatinase A; Genes; Glioblastoma; Glioma; Growth; Health; Human; Immigration; Immune response; In Vitro; Inhibition of Matrix Metalloproteinases Pathway; Intracranial Neoplasms; Invaded; Laboratories; MMP2 gene; Maintenance; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Matrix Metalloproteinases; Membrane Proteins; Messenger RNA; Modality; Molecular; Morbidity - disease rate; Neoplasm Metastasis; Nude Mice; Oligonucleotides; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Primary Brain Neoplasms; Process; RNA Interference; Radiation; Radiation therapy; Radiosurgery; Recurrence; Refractory; Research; Residual state; Resistance; Role; Small Interfering RNA; Specificity; Survival Rate; Survivors; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Treatment outcome; Tumor Cell Invasion; angiogenesis; base; brain tissue; cancer cell; cancer therapy; cell growth; effective therapy; improved; in vitro Model; in vivo; in vivo Model; inhibitor/antagonist; insight; irradiation; malignant phenotype; migration; mortality; neoplastic cell; novel; novel therapeutic intervention; outcome forecast; treatment effect; tumor; tumor growth; tumor progression; vector; vector control

DESCRIPTION (provided by applicant): Malignant brain tumors represent one of the most refractory cancers to therapy and remain incurable. Gliomas represent the most common type of brain tumors and occur in various grades, with the patient's prognosis inversely proportional to grade. 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. Despite some 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 MMP-2 in malignant gliomas or glioblastomas. We hopothesize that the MMP-2 gene will be targeted while simultaneously combined with radiation and their anti-cancer effects will be determined. The specific aims of this proposal are: Specific Aim 1. Evaluate the effect of p-MMP-2 construct and irradiation alone, or in combination, on glioma cell growth, invasion and angiogenesis in both in vitro and in vivo models. Aim 1a. Determine the effect of p-MMP-2 and irradiation alone, or in combination, on the levels of MMP-2 in glioblastoma cell lines. Aim 1b. Determine the effect of p-MMP-2 and irradiation alone, or in combination, on the invasive behavior of human glioblastoma cell lines in in vitro models with that of controls/mock and SV (scrambled vector). Aim 1c. Evaluate the effect of p-MMP-2 and irradiation alone, or in combination, on cerebral angiogenesis both in vitro and in vivo. Aim 1d. Determine the optimal doses of p-MMP-2 and irradiation alone, or in combination, on pre-established intracranial tumor growth or invasiveness of human glioblastoma cell lines injected intracerebrally in nude mice. Specific Aim 2. Determine the effect of p-MMP-2 and irradiation alone, or in combination, on the molecular mechanisms of proliferation, migration, adhesion and apoptosis in glioblastoma cell lines. Aim 2a. Investigate the effect of p-MMP-2 and irradiation alone, or in combination, on the molecular mechanisms of adhesion and migration in glioblastoma cell lines compared to control/mock and p-SV controls. Aim 2b. Determine the effect of p-MMP-2 and irradiation alone, or in combination, on the molecular mechanisms of proliferation in glioblastoma cell lines compared with mock and p-SV. Aim 2c. Evaluate the effect of p-MMP-2 and irradiation alone, or in combination, on the molecular mechanisms of apoptosis in glioblastoma cell lines compared with mock and p-SV. The proposed studies should generate major insights into the pathogenesis of radiation-induced alteration in tumor after inhibition of MMP-2 and, in turn, should suggest novel targets for therapeutic interventions of glioblastomas. PUBLIC HEALTH RELEVANCE: Despite the many therapeutic strategies undertaken for treatment of glioblastoma multiforme, the survival rate for patients afflicted with this aggressive cerebral malignancy remains low. Involved-field radiotherapy has remained the single most effective therapy of glioblastoma for more than 25 years. 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 p-MMP-2 siRNA. This strategy may improve radiotherapy outcomes for the treatment of glioblastomas.

描述（由申请人提供）：恶性脑肿瘤是治疗最难治性的癌症之一，并且仍然无法治愈。神经胶质瘤是最常见的脑肿瘤类型，并且发生在各种等级中，患者的预后与等级成反比。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，也可能会出现与辐射相关的副作用的关注。尽管有一些治疗作用，但最近的证据表明，通过激活参与肿瘤侵袭性，血管生成和转移的几种途径，可以在体外和体内促进癌细胞的恶性行为。包括我们的一些研究，包括我们的恶性神经胶质瘤或胶质母细胞瘤中MMP-2的水平显着升高。我们认为，MMP-2基因将被靶向，同时与辐射结合，并确定其抗癌作用。该提案的具体目的是：特定目标1。在体外和体内模型中，评估单独或联合辐照，单独或组合对胶质瘤细胞生长，侵袭和血管生成的影响。目标1a。确定P-MMP-2和单独辐照或组合对胶质母细胞瘤细胞系中MMP-2水平的影响。目标1B。在体外模型中，与对照/模拟和SV的体外模型中，单独或组合辐射对人胶质母细胞瘤细胞系的侵入性行为（炒载体）的侵入性行为。 AIM 1C。评估P-MMP-2和单独辐照或组合对体外和体内脑血管生成的影响。目标1d。确定P-MMP-2的最佳剂量和单独的辐照或组合，以预先建立的颅内肿瘤生长或人胶质母细胞瘤细胞系注入裸鼠的脑内毛细胞细胞系的侵入性。具体目的2。确定胶质母细胞瘤细胞系中P-MMP-2和单独或联合辐射对增殖，迁移，粘附和凋亡的分子机制的影响。目标2a。与对照/模拟和P-SV对照相比，研究P-MMP-2和单独辐照或组合对胶质母细胞瘤细胞系粘附和迁移的分子机制的影响。目标2B。与模拟和p-SV相比，仅确定P-MMP-2和单独辐照或组合对胶质母细胞瘤细胞系增殖的分子机制的影响。 AIM 2C。与模拟和P-SV相比，评估P-MMP-2和单独辐照或组合对胶质母细胞瘤细胞系凋亡的分子机制的影响。拟议的研究应产生对MMP-2抑制后辐射诱导的肿瘤改变的发病机理的主要见解，进而提出了用于胶质母细胞瘤治疗干预措施的新靶标。公共卫生相关性：尽管采取了许多治疗多种胶质母细胞瘤的治疗策略，但患有这种侵略性大脑恶性肿瘤的患者的存活率仍然很低。涉及场放射疗法一直是胶质母细胞瘤的最有效疗法已有25年以上。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。该建议代表了使用P-MMP-2 siRNA的组合治疗方法。该策略可以改善用于治疗胶质母细胞瘤的放射治疗结果。

项目成果

Suppression of MMP-2 attenuates TNF-α induced NF-κB activation and leads to JNK mediated cell death in glioma.

• DOI: 10.1371/journal.pone.0019341
• 发表时间: 2011-05-04
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Kesanakurti D;Chetty C;Bhoopathi P;Lakka SS;Gorantla B;Tsung AJ;Rao JS
• 通讯作者: Rao JS

Essential role of cooperative NF-κB and Stat3 recruitment to ICAM-1 intronic consensus elements in the regulation of radiation-induced invasion and migration in glioma.

• DOI: 10.1038/onc.2012.546
• 发表时间: 2013-10-24
• 期刊: ONCOGENE
• 影响因子: 8
• 作者: Kesanakurti, D.;Chetty, C.;Maddirela, D. Rajasekhar;Gujrati, M.;Rao, J. S.
• 通讯作者: Rao, J. S.

Functional cooperativity by direct interaction between PAK4 and MMP-2 in the regulation of anoikis resistance, migration and invasion in glioma.

• DOI: 10.1038/cddis.2012.182
• 发表时间: 2012-12-20
• 期刊: Cell death & disease
• 影响因子: 9

Role of MMP-2 in the regulation of IL-6/Stat3 survival signaling via interaction with α5β1 integrin in glioma.

• DOI: 10.1038/onc.2012.52
• 发表时间: 2013-01-17
• 期刊: ONCOGENE
• 影响因子: 8
• 作者: Kesanakurti, D.;Chetty, C.;Dinh, D. H.;Gujrati, M.;Rao, J. S.
• 通讯作者: Rao, J. S.

MMP-2 siRNA inhibits radiation-enhanced invasiveness in glioma cells.

• DOI: 10.1371/journal.pone.0020614
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Badiga AV;Chetty C;Kesanakurti D;Are D;Gujrati M;Klopfenstein JD;Dinh DH;Rao JS
• 通讯作者: Rao JS