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）是一种毁灭性的疾病，每年造成约18，000名美国人死亡。GBM患者 用替莫唑胺和电离辐射（IR）治疗，但肿瘤总是复发。分子 在GBM中驱动治疗抗性的机制是未知的。分子靶向治疗，包括EGFR 和VEGF抑制剂未能延长GBM中令人沮丧的（15个月中位）存活期。基于我们之前 工作，NF-κ B B信号传导和放射抗性在GBM的某些亚型中的直接致癌作用已经被证实。 发现了最近，一项独立的研究证实了抑制GBM中NF-κ B B信号传导的功效。 因此，我们假设抑制NF-κ B B信号传导可以提高GBM的存活率.尽管如此， 关于NF-κ B B抑制剂的功效和它们抑制肿瘤生长的机制的知识缺口 GBM的各种分子亚型。应用的前提是测试作用机制， 一种新的自催化脑肿瘤靶向（ABTT）纳米颗粒递送的疗效和治疗益处 NF-κ B B通路抑制剂DTP 3的作用。 在Aim 1中，我们将研究三肽DTP 3在GBM临床前模型中的凋亡作用，并研究 其作用机制。由于DTP 3通过抑制NF-κ B调节的抗凋亡蛋白的相互作用发挥作用， 我们将检测caspase 3的激活和JNK的磷酸化， 读取MKK 7激活。在目标2中，我们将测试ABTT-DTP 3作为单一药剂的治疗益处， 以及在GBM的分子亚型中与分次辐射的组合。主要终点为总体终点 存活率和生物发光图像引导肿瘤体积测量。作用机制将是 通过定量评估体内肿瘤增殖、体内肿瘤侵袭、组织病理学 固定组织检查和JNK磷酸化检查。这项建议的一个关键优点是， 我们将利用纳米颗粒介导的肽递送来特异性靶向NF-κ B的抗凋亡功能， 脑肿瘤中的B超B。这是第一次使用临床试验对NF-κ B B的癌症特异性阻断进行全面表征， 神经胶质瘤的相关患者衍生模型将为使用NF-κ B B阻断剂在神经胶质瘤中的临床试验提供基础。 GBM。