Regression of meningioma tumor growth by combination therapy

描述（由申请人提供）：联合治疗脑膜瘤肿瘤生长消退15%的脑膜瘤具有恶性特征，这些侵袭性肿瘤通常是致命的。放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。对于残留或复发的良性肿瘤患者，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方法，如放射外科手术，也可能发生。除了治疗效果外，近年来的研究表明，辐照可能通过激活肿瘤侵袭、血管生成和转移等多种途径，在体外和体内促进癌细胞的恶性行为。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的水平显著升高。为了确定辐射与脑膜瘤中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的：具体目的1：确定各种siRNA双链结构物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：确定不同siRNA双链结构结合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。目的1b：评价不同siRNA双链结构物联合辐照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双链构建体联合照射对脑膜瘤细胞株凋亡分子机制的影响。目的1d：确定不同siRNA双链结构体联合照射对脑膜瘤细胞株粘附、迁移和侵袭的影响。特异性目的2：评价不同双链siRNA构建物联合照射治疗对裸鼠脑膜瘤肿瘤生长和血管生成的影响。目的2a：确定在没有照射的情况下，在裸鼠脑内注射各种双电siRNA结构物的最佳剂量，以抑制预先建立的颅内肿瘤生长或人脑膜瘤细胞系的侵袭性。目的2b：确定不同双声siRNA构建物联合照射对裸鼠颅内肿瘤生长的影响。目的2c：评价不同双链siRNA构建物单独或联合照射对体外和体内脑血管生成的影响。拟议的研究应该对肿瘤的辐射诱导改变的发病机制产生重要的见解，反过来，应该为脑膜瘤的治疗干预提出新的靶点。公共卫生相关性：15%的脑膜瘤具有恶性特征，这些侵袭性、侵袭性肿瘤通常是致命的。放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，越来越多的长期幸存者在这种治疗中出现了继发性副作用，这凸显了开发新的治疗方法的必要性。该建议代表了一种使用双频siRNA的联合治疗方法。这种策略可以改善脑膜瘤的放疗效果。

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.