Developing a NF-κB/GADD45b targeting strategy for glioblastoma

项目总结 胶质母细胞瘤(GBM)是一种毁灭性的疾病，每年导致约18,000名美国人死亡。GBM患者是 用替莫唑胺和电离辐射(IR)治疗，但肿瘤总是复发。分子 导致GBM耐药的机制尚不清楚。包括EGFR在内的分子靶向治疗 和血管内皮生长因子抑制剂，都未能延长GBM患者令人沮丧的(15个月中位数)生存期。基于我们之前的 研究表明，在某些基底膜亚型中，核因子-B信号和放射抗性具有直接致癌作用。 没有遮盖物。最近，一项独立的研究证实了抑制基底膜中NF-B信号转导的有效性。 因此，我们假设抑制NF-B信号可以提高基底膜的存活率。尽管如此，还是有一个 关于核因子-B抑制剂的疗效及其抑制肿瘤生长的机制的认识空白 GBM的各种分子亚型。应用的前提是检验作用机制， 一种新型自催化脑肿瘤靶向(ABTT)纳米粒的疗效和治疗效益 一种核因子-B途径抑制物，DTP3。 在Aim1中，我们将研究一种名为DTP3的三肽在GBM临床前模型中的凋亡作用，并研究 它的作用机制。因为DTP3通过抑制核因子-κB调节的抗细胞凋亡的相互作用而发挥作用 因子GADD45JNK与MKK7结合，我们将检测caspase3的激活和β的磷酸化 读出MKK7激活。在目标2中，我们将测试ABTT-DTP3作为单一药物的治疗效果。 以及在GBM的分子亚型中与分次辐射的组合。主要终端将是整体的 存活率和生物发光--图像引导的肿瘤体积测量。行动机制将是 通过定量评估体内肿瘤增殖、体内肿瘤侵袭、组织病理学 固定组织检查，JNK磷酸化检查。这项提议的一个关键优点是 我们将利用纳米颗粒介导的多肽递送来特异性地靶向核因子-2的抗凋亡功能。 脑肿瘤中的B。首次使用临床方法全面表征肿瘤特异性阻断核因子-B 相关患者来源的胶质瘤模型将为使用NF-B阻断脑胶质瘤的临床试验提供基础 GBM。

PROJECT SUMMARY Glioblastoma (GBM) is a devastating disease that kills about 18,000 Americans every year. GBM patients are treated with temozolamide and ionizing radiation (IR), but the tumor invariably recurs. The molecular mechanisms driving treatment resistance in GBM are unknown. Molecular targeted therapies including EGFR and VEGF inhibitors, have failed to extend the dismal (15 month median) survival in GBM. Based on our previous work, a direct oncogenic role of NF-B signaling and radio-resistance in some subtypes of GBM has been uncovered. Recently, an independent study validated the efficacy of inhibiting NF-B signaling in GBM. Therefore, we hypothesize that inhibition of NF-B signaling improves survival in GBM. Nonetheless, there is a gap in knowledge regarding the efficacy of NF-B inhibitors and the mechanisms by which they inhibit growth of the various molecular subtypes of GBM. The premise of the application is to test the mechanism of action, efficacy, and the therapeutic benefit of a novel autocatalytic brain tumor-targeted (ABTT) nanoparticle delivery of a NF-B pathway inhibitor, DTP3. In Aim1 we will examine the apoptotic effects of a tripeptide, DTP3, in GBM preclinical models and investigate its mechanism of action. Because DTP3 functions by inhibiting interaction of the NF-κB-regulated anti-apoptotic factor GADD45β with MKK7, we will examine the activation of caspase 3 and the phosphorylation of JNK as a read out of MKK7 activation. In Aim 2 we will test the therapeutic benefits of ABTT-DTP3 as a single agent as well as a combination with fractionated radiation in molecular subtypes of GBM. Primary end-points will be overall survival and bioluminescence-image-guided tumor volume measurement. Mechanism of action will be determined by quantitative assessment of in vivo tumor proliferation, in vivo tumor invasion, histopathological examination of fixed tissue, and examination of JNK phosphorylation. A critical strength of this proposal is that we will utilize a nanoparticle mediated delivery of a peptide to specifically target anti-apoptotic functions of NF- B in brain tumors. This first comprehensive characterization of cancer specific blockade of NF-B using clinical relevant patient derived models of glioma will provide the foundation for clinical trials using NF-B blockade in GBM.