Regression of meningioma tumor growth by combination therapy

描述（由申请人提供）：联合治疗使脑膜瘤肿瘤生长消退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，人们越来越关注放射相关的副作用，即使使用高度精确的治疗（如放射外科）也可能发生这些副作用。近年来的研究表明，辐射不仅具有治疗作用，还可通过激活肿瘤侵袭、血管生成和转移等多种途径，在体内外促进肿瘤细胞的恶性行为。包括我们在内的几项研究表明，恶性脑膜瘤中uPA、uPAR、MMP- 9和组织蛋白酶B水平显著升高。为了确定放射与脑膜瘤中uPA、uPAR、MMP-9和组织蛋白酶B之间的分子相互作用，我们提出了以下具体目标：具体目标1：确定各种siRNA双顺反子构建体与放射相结合对脑膜瘤细胞体外生长、附着、凋亡、迁移和侵袭的影响。目标1a：确定各种siRNA双顺反子构建体与辐射组合对脑膜瘤细胞系中uPA、uPAR、MMP-9和组织蛋白酶B水平的影响。目标1b：评价各种siRNA双顺反子构建体联合放射对脑膜瘤细胞系增殖的分子机制的影响。目标1c：研究各种siRNA双顺反子构建体结合放射对脑膜瘤细胞系凋亡分子机制的影响。目标1d：确定各种siRNA双顺反子构建体与辐射组合对脑膜瘤细胞系中的粘附、迁移和侵袭的影响。具体目标二：评价各种双顺反子siRNA构建体与放射治疗组合对裸鼠中脑膜瘤肿瘤生长和血管生成的影响。目标2a：确定在不存在辐射的情况下各种双顺反子siRNA构建体抑制预先建立的颅内肿瘤生长或裸鼠脑内注射的人脑膜瘤细胞系的侵袭性的最佳剂量。目标2b：确定各种双顺反子siRNA构建体与照射组合对裸鼠中预先建立的颅内肿瘤生长的影响。目标2c：评价各种双顺反子siRNA构建体单独或与辐射组合在体外和体内对脑血管生成的作用。拟议中的研究应产生重大的见解辐射诱导的肿瘤变化的发病机制，反过来，应该建议脑膜瘤的治疗干预的新目标。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。然而，越来越多的长期生存者与继发性副作用，从这种治疗强调需要开发新的治疗方法。该提议代表了使用双顺反子siRNA的组合治疗方法。这种策略可能会改善脑膜瘤的放射治疗效果。

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.