Targeting MACF1 in Glioblastoma

项目摘要/摘要 目前用于治疗临床胶质母细胞瘤的放化疗方案的特异性 对于这种疾病的治疗，保留正常的细胞和组织仍然是一个警告。这一期 是由具有不同遗传特征的胶质母细胞瘤的亚型组成的，因此有必要确定 这些癌症的新的未确定的治疗靶点。靶向治疗方法的实用性 因此，由于其选择性，提供了比标准临床治疗方式更大的临床益处 和专一性。靶向治疗对恶性脑肿瘤的治疗尤为有利。 肿瘤作为绕过这些肿瘤的细胞和分子异质性的一种手段，这种异质性有助于 其复发率高，治疗耐药。像大多数人类癌症一样，侵袭性 胶质母细胞瘤的持续增殖是由细胞骨架蛋白控制的。这项研究的目的是 目的是评估微管肌动蛋白交联因子(MACF1)，一种细胞骨架整合蛋白，在 胶质母细胞瘤。MACF1作为恶性脑肿瘤治疗靶点的评价是基于初步的 来自拟议工作的数据支持MACF1有助于维护和 恶性脑肿瘤的进展，并将以两个特定的目标来解决：1)确定MACF1是 胶质母细胞瘤的抑制靶点及其致瘤作用；2)评价MACF1 AS的抑制靶点 一种治疗胶质母细胞瘤的化学增敏剂。基因抑制和过度表达实验将被用来评估 MACF1在胶质母细胞瘤中的抗肿瘤靶向性和致瘤性及其生物标志物的表达 MACF1的分析将在患者的各种胶质瘤中进行。进一步研究沉默MACF1的效果 功能将作为化疗药物替莫唑胺的增敏剂进行评估。建议数 研究既有创新性又有意义，因为拮抗MACF1功能提供了一个单一的靶点 将损害两个不同群体的增殖和迁移侵袭细胞的特性，这两种细胞有助于 胶质母细胞瘤的持续和复发；以及识别一个特征不明的扩大的靶点 我们的方法不仅抗击胶质母细胞瘤，而且还抗击其他癌症，这些癌症将在1/2被诊断为 人在有生之年。

PROJECT SUMMARY/ABSTRACT The specificity of current chemo- and radiation therapy protocols used to treat clinical glioblastomas while sparing normal cells and tissues has remained a caveat for therapeutic treatments of this disease. This issue is compounded by the subtypes of glioblastoma with varying genetic profiles, making it necessary to identify novel uncharacterized therapeutic targets in these cancers. The utility of a targeted therapy approach therefore offers greater clinical benefit over standard clinical treatment modalities because of its selectivity and specificity. A targeted therapy approach is particularly advantageous for the treatment of malignant brain tumors as a means to circumvent the cellular and molecular heterogeneity of these tumors which contribute to their high rates of recurrence and therapeutic resistance. Like most human cancers the invasive nature and continued propagation of glioblastoma are governed by cytoskeletal proteins. The objective of this study is to assess Microtubule Actin Cross-Linking Factor (MACF1), a cytoskeletal integrator protein, for its role in glioblastoma. Evaluation of MACF1 as a therapeutic target in malignant brain tumors is based on preliminary data from the proposed work that supports the hypothesis that MACF1 contributes to the maintenance and progression of malignant brain tumors and will be addressed with two specific aims: 1) To ascertain MACF1 as an inhibitory target and its tumorigenic role in glioblastoma and 2) To evaluate inhibitory targeting of MACF1 as a chemosensitizer in glioblastoma. Genetic inhibitory and overexpression experiments will be used to assess anti-tumorigenic targeting and tumorigenic properties of MACF1 in glioblastoma, while biomarker expression analysis of MACF1 will be performed on various gliomas from patients. Further the effects of silencing MACF1 function will be evaluated as a sensitizer of the chemotherapeutic agent, temozolomide. The proposed research is both innovative and significant because antagonizing MACF1 function provides a single target that will impair properties of two distinct populations of proliferating and migratory invasive cells that contribute to the perpetuation and recurrence of glioblastoma; as well as identify an uncharacterized target that expands our approach to combating not only glioblastoma but other cancers that will be diagnosed in 1 out 2 persons during their lifetime.