Targeting Glioma by Anti-MMPs-2 and -9 DNAzymes

描述（由申请人提供）：尽管在诊断、手术技术和放射方案方面不断改进，但对高度恶性胶质瘤的可用治疗仍然严重不足。大多数高级别胶质瘤患者的中位生存时间为数月。因为手术是目前唯一能为这些患者提供一些益处的治疗方法，所以开发一种有效的手术辅助剂确实可以使平衡朝着更好的结果倾斜。多形性胶质母细胞瘤是最常见的恶性脑肿瘤，其特征在于存在坏死、血管增生和侵袭周围正常脑组织。虽然促进脑癌侵袭行为的具体机制尚不清楚，但已知肿瘤细胞侵袭至少部分是通过肿瘤细胞和基质细胞产生的中性金属蛋白酶（MMP）降解基底膜介导的。有证据表明，MMP-2和MMP-9在CNS肿瘤细胞的侵袭和转移中起重要作用。最近，我们已经表明，针对MMP-2或MMP-9 mRNA产生的DNAzyme能够在体外减少酶的表达，以及在体内动物模型中产生的C6-胶质瘤的大小。考虑到其全身给药和靶向的潜力，DNA酶可以被证明是有用的，作为一种针对胶质瘤侵袭的治疗靶向MMPs。为了实现这一目标，1。通过在大鼠颅内神经胶质瘤模型中对DNAzyme进行剂量递增和时程研究，确定完全根除肿瘤而不对脑的周围健康组织引起显著毒性所需的DNAzyme的最小有效剂量。我们将同时评估DNA酶在健康CNS组织中的安全性和生物利用度。2.将在大鼠异种移植颅内神经胶质瘤模型中测试DNAzyme治疗人神经胶质瘤的功效。三。评估DNA酶治疗对携带神经胶质瘤的动物的预期寿命（存活率）的影响。因此，在本研究中，我们通过研究抗MMP-2和MMP-9 DNA酶治疗对发病率和死亡率的主要机制的影响，采取了一种创新的方法来治疗胶质瘤。

DESCRIPTION (provided by applicant): Despite continued improvements in diagnosis, surgical techniques, and radiation protocols, the available treatments for high-grade malignant glioma are grossly inadequate. The median survival time for most patients with high-grade gliomas is on the order of months. Because surgery is the only therapy currently available that provides some benefit for these patients, the development of a potent adjuvant to surgery could indeed tip the balance towards a better outcome. The most common and malignant brain tumor, glioblastoma multiforme, is characterized by the presence of necrosis, vascular proliferation, and aggressive invasion into surrounding normal brain tissue. Although the specific mechanisms facilitating the invasive behaviors of brain cancer are unclear, tumor cell invasion are known to be mediated, at least in part, through degradation of basement membrane by neutral metalloproteinases (MMP) produced by tumor cells and stroma cells. Evidence suggests that MMP-2 and MMP-9 play a significant role in CNS tumor cell invasion and metastasis. Recently, we have shown that DNAzyme generated against either MMP-2 or MMP-9 mRNA was able to reduce the expression of the enzymes in vitro, as well as the size of the C6-glioma generated in the in vivo animal model. Given their potential for systemic administration and targeting, DNAzymes could prove useful as a therapy against Glioma invasion by targeting MMPs. Toward achievement of this goal, 1. the minimum effective dose of DNAzyme needed to completely eradicate the tumor without causing significant toxicity to the surrounding healthy tissue of the brain will be determined by a dose escalation and a time course study of DNAzyme in the rat intracranial glioma model. We will simultaneously evaluate the safety and bioavailability of DNAzymes in healthy CNS tissues. 2. the efficacy of DNAzyme in treating human glioma will be tested in rat xenograft intracranial glioma model. And, 3. the effect of DNAzymes treatment on life expectancy (survival rate) of the animals bearing glioma will be assessed. Thus, in this proposal we are taking an innovative approach to the treatment of glioma by studying the effect the anti MMP-2 and MMP-9 DNAzymes therapy on the major mechanism of morbidity and mortality.