Regression of meningioma tumor growth by combination therapy

描述(申请人提供)：脑膜瘤肿瘤生长通过联合治疗的消退15%的脑膜瘤具有恶性特征，这些侵袭性侵袭性肿瘤通常是致命的。放射治疗仍然是控制恶性和良性脑膜瘤治疗方式的主要组成部分。在残留或复发的良性肿瘤患者中，人们越来越担心放射相关的副作用，即使在放射外科等高度精确的治疗下也可能发生这些副作用。除了治疗作用外，最近的证据表明，辐射可能通过激活与肿瘤侵袭、血管生成和转移有关的几条途径，促进肿瘤细胞在体外和体内的恶性行为。几项研究，包括我们的研究，显示恶性脑膜瘤中uPA、uPAR、基质金属蛋白酶-9和组织蛋白酶B的水平显著升高。为了确定辐射与脑膜瘤中uPA、uPAR、基质金属蛋白酶-9和组织蛋白酶B之间的分子相互作用，我们提出了以下特定目标：特定目标1：确定不同siRNA双顺反子结构与辐射联合对脑膜瘤细胞生长、附着、凋亡、迁移和侵袭的影响。目的1a：探讨不同siRNA双顺反子载体联合照射对脑膜瘤细胞uPA、uPAR、基质金属蛋白酶-9和组织蛋白酶B表达水平的影响。目的1b：探讨不同siRNA双顺反子构建物联合辐射对脑膜瘤细胞系增殖的分子机制的影响。目的1c：探讨不同siRNA双顺反子结构与辐射联合作用对脑膜瘤细胞系凋亡分子机制的影响。目的1D：探讨不同siRNA双顺反子构建物联合辐射对脑膜瘤细胞系黏附、迁移和侵袭的影响。具体目的2：评价不同双顺反子siRNA构建物联合放射治疗对脑膜瘤裸鼠移植瘤生长和血管生成的影响。目的2a：确定不同双顺反子siRNA构建物在无照射条件下抑制裸鼠脑内注射的人脑膜瘤细胞系的生长或侵袭的最佳剂量。目的2b：探讨不同双顺反子siRNA构建物联合放射治疗对已建立的裸鼠颅内肿瘤生长的影响。目的2c：在体内外评价不同双顺反子siRNA构建物单独或联合辐射对脑血管生成的影响。拟议的研究应该会对辐射诱导的肿瘤改变的发病机制产生重要的见解，并反过来应该为脑膜瘤的治疗干预提供新的靶点。公共卫生相关性：15%的脑膜瘤具有恶性特征，这些侵袭性、侵袭性肿瘤往往是致命的。放射治疗仍然是控制恶性和良性脑膜瘤治疗方式的主要组成部分。然而，越来越多的长期生存者因这种治疗而产生二次副作用，这突显了开发新的治疗方法的必要性。这项建议代表了一种使用双顺反子siRNA的联合治疗方法。这一策略可能会改善脑膜瘤治疗的放射治疗结果。

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.