Developing a NF-κB/GADD45b targeting strategy for glioblastoma

制定胶质母细胞瘤的 NF-κB/GADD45b 靶向策略

• 批准号: 9901485
• 负责人: KRISHNA PL BHAT
• 金额: $ 17.64万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9901485
• 关键词: Address; American; Apoptosis; Apoptotic; Automobile Driving; Binding; Brain; Brain Neoplasms; CASP3 gene; Cancer Center; Clinical; Clinical Trials; Disease; Doctor of Medicine; Drug Delivery Systems; Encapsulated; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Foundations; GADD45A gene; GADD45B; Glioblastoma; Glioma; Growth; Homeostasis; Immunity; Immunohistochemistry; In Vitro; Ionizing radiation; JNK-activating protein kinase; Knowledge; Laboratories; MAPK8 gene; Malignant Neoplasms; Malignant neoplasm of brain; Measurement; Mediating; Mesenchymal; Modeling; Molecular; Molecular Target; Multiple Myeloma; Mus; NF-kappa B; New Agents; Newly Diagnosed; Oncogenic; Pathway interactions; Patients; Penetrance; Penetration; Peptides; Pharmacology; Phosphorylation; Play; Pre-Clinical Model; Reagent; Recurrence; Regulation; Role; Signal Pathway; Signal Transduction; Specificity; TNF gene; Tertiary Protein Structure; Testing; Therapeutic; Tissues; Tumor Biology; Tumor Cell Invasion; Tumor Subtype; Tumor Volume; Universities; Vegf Inhibitor; Work; Xenograft Model; Xenograft procedure; base; bioluminescence imaging; cancer cell; clinically relevant; efficacy testing; experimental study; fractionated radiation; histopathological examination; image guided; improved; in vitro testing; in vivo; in vivo Model; inhibitor/antagonist; interest; molecular subtypes; molecular targeted therapies; mouse model; nanoparticle; nanoparticle delivery; neoplastic cell; novel; p65; peptide B; primary endpoint; radiation resistance; side effect; stem-like cell; systemic toxicity; temozolomide; therapeutic evaluation; therapy resistant; tumor

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.

项目摘要 胶质母细胞瘤（GBM）是一种毁灭性疾病，每年杀死约18,000名美国人。 GBM患者是 用替莫唑胺和电离辐射（IR）处理，但肿瘤总是复发。分子 驾驶GBM耐药性的机制尚不清楚。包括EGFR在内的分子靶向疗法 VEGF抑制剂未能扩大GBM的惨淡（15个月中位数）生存。根据我们以前的 工作，NF-B信号传导和抗性的直接致癌作用已在某些GBM的亚型中是 裸露。最近，一项独立研究验证了抑制GBM中NF-B信号传导的效率。 因此，我们假设抑制NF-B信号传导可改善GBM的存活率。但是，有一个 关于NF-B抑制剂效率的知识差距以及它们抑制生长的机制 GBM的各种分子亚型。应用程序的前提是测试作用机理， 功效以及新型自催化脑肿瘤（ABTT）纳米颗粒递送的治疗益处 NF-B途径抑制剂的DTP3。 在AIM1中，我们将检查三肽DTP3在GBM临床前模型中的凋亡效应并研究 它的作用机理。因为DTP3通过抑制NF-κB调节的抗凋亡的相互作用来发挥作用 用MKK7的因子GADD45β，我们将检查caspase 3的激活和JNK的磷酸化作为A 从MKK7激活中读取。在AIM 2中，我们将测试ABTT-DTP3作为单一代理的治疗益处 以及GBM分子亚型中分离辐射的组合。主要终点总体上将 生存和生物发光 - 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，组织病理学确定 检查固定组织和JNK磷酸化的检查。该提议的关键优势是 我们将利用纳米颗粒介导的肽的递送来专门针对NF-的抗凋亡功能 B中的B。使用临床对癌症特异性封锁的第一个全面表征 相关患者衍生的神经胶质瘤模型将为临床试验提供基础 GBM。