Targeting MACF1 in Glioblastoma

项目总结/摘要 目前用于治疗临床胶质母细胞瘤的化疗和放疗方案的特异性， 保留正常细胞和组织仍然是治疗这种疾病的注意事项。这个问题 是复杂的胶质母细胞瘤亚型与不同的遗传概况，使其有必要确定 这些癌症中的新的未表征的治疗靶点。靶向治疗方法的效用 因此，由于其选择性， 和特异性。靶向治疗方法对于恶性脑肿瘤的治疗特别有利。 肿瘤作为一种手段来规避这些肿瘤的细胞和分子异质性， 他们的高复发率和治疗抗性。像大多数人类癌症一样， 胶质母细胞瘤的持续增殖受细胞骨架蛋白的控制。本研究的目的 是评估微管肌动蛋白交联因子（MACF 1），一种细胞骨架整合蛋白， 胶质母细胞瘤MACF 1作为恶性脑肿瘤治疗靶点的评价是基于初步的 来自支持MACF 1有助于维持的假设的拟议工作的数据， 恶性脑肿瘤的进展，并将解决两个具体目标：1）确定MACF 1作为 抑制性靶点及其在胶质母细胞瘤中的致瘤作用，以及2）评估MACF 1的抑制性靶向作用， 胶质母细胞瘤的化疗增敏剂。遗传抑制和过表达实验将用于评估 MACF 1在胶质母细胞瘤中的抗致瘤靶向和致瘤特性，而生物标志物表达 将对来自患者的各种神经胶质瘤进行MACF 1分析。沉默MACF 1的效果 将作为化疗剂替莫唑胺的敏化剂来评价功能。拟议 这项研究是创新性的和重要的，因为拮抗MACF 1功能提供了一个单一的靶点， 将损害两种不同的增殖和迁移侵袭细胞群体的特性， 胶质母细胞瘤的持续和复发;以及确定一个未表征的目标， 我们的方法不仅打击胶质母细胞瘤，但其他癌症，将被诊断出1 2 人的一生。

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.