Strategies to improve the antiglioma action of IFN-?: a role for NF-kB inhibition

改善 IFN-α 抗神经胶质瘤作用的策略：抑制 NF-kB 的作用

• 批准号: 8020141
• 负责人: ANDREW M DAVIDOFF
• 金额: $ 51.06万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8020141
• 关键词: Adjuvant; Angiopoietin-1; Apoptosis; Apoptotic; Binding; Brain Neoplasms; Cancer Etiology; Cell Death; Cell Survival; Cells; Cessation of life; Clinical; Clinical Trials; Combined Modality Therapy; Cytoplasm; DNA; DNA Repair Enzymes; Disease; Down-Regulation; Effectiveness; Evaluation; Excision; Gene Targeting; Genetic; Glioblastoma; Glioma; Goals; Health; In Vitro; Interferon-beta; Interferons; MGMT gene; Malignant Glioma; Malignant Neoplasms; Mediating; NF-kappa B; Nuclear; Operative Surgical Procedures; Pathway interactions; Patients; Pre-Clinical Model; Proteins; Radiation therapy; Resistance development; Rodent Model; Role; Site; TNF-related apoptosis-inducing ligand; Testing; Therapeutic; Transferase; Translating; United States; Work; XAF1 gene; angiogenesis; anticancer activity; base; cell type; chemotherapy; cytokine; efficacy testing; gene induction; glioma cell line; human BIRC4 protein; improved; in vivo; inhibitor/antagonist; insight; novel strategies; pre-clinical; response; tumor; tumor progression

DESCRIPTION (provided by applicant): Brain tumors are among the leading causes of cancer-related deaths in the United States, with glioblastoma multiforme (GBM) being one of the most aggressive and difficult subtypes to treat. In this proposal we plan to pursue a strategy to treat malignant glioma with the potent antitumor cytokine, interferon-beta (IFN2). Type I (1/2) interferons (IFNs) have long been recognized for their significant, pleiotropic anticancer activity. However, despite significant activity in preclinical models against a variety of tumor types, including gliomas, the antitumor efficacy of IFNs in clinical trials has been disappointing. A significant contributing factor includes the development of resistance to IFN-mediated cell death through downregulation of apoptotic pathways. We have established that nuclear factor kB (NFkB) promotes cell survival and suppresses the expression of a subset of IFN target genes that are likely effectors of IFN's antitumor activity. Unfortunately, not only is NFkB constitutively active in many cancers, including glioma, but it can also be activated by IFN itself. This finding suggests that the potent anticancer activity of IFN may be counterbalanced by NFkB activity. Based on these observations, we hypothesize that selective inhibition of NFkB will enhance the anticancer activity of IFN. We will perform a systematic and detailed evaluation of the role of NFkB in regulating the anticancer action of IFN2 in glioma cells. Based on the insights gained, we will select and test complementary agents that should provide synergistic antitumor activity with IFN. After confirming the synergy of these agents in vitro, we will test the effectiveness of combination therapy that includes IFN in relevant preclinical models of malignant glioma. The overriding goal of this project is to increase the antitumor activity of IFN through an improved understanding of IFN2's mechanism of action against glioma and the factors that work against it. In specific aim 1 we will examine the role of NFkB in suppressing the anticancer activity of IFN2 in gliomas. To test this, we will determine in glioma cell lines 1) the contribution of the classical NF:B pathway to constitutive and IFN-induced NF:B activity; 2) the contribution of the alternative NF:B pathway to constitutive and IFN-induced NF:B activity; and 3) the effects of pharmacological and genetic NF:B inhibitors on IFN activity. Based on these findings, we will test the effects of clinically available NFkB inhibitors on IFN's anticancer activity in relevant, preclinical rodent models of malignant glioma. In specific aim 2 we will characterize the role of NFkB in regulating IFN target genes and the role of these target genes in the anticancer action of IFN2 in gliomas. To test this, we will: 1) characterize the induction of these genes in response to IFN; 2) determine their importance in effecting the anticancer activity of IFN in vitro and in vivo and 3) translate these findings by testing the efficacy of appropriately selected combination therapy in relevant, preclinical models of malignant glioma. PUBLIC HEALTH RELEVANCE: Brain tumors are among the leading causes of cancer-related deaths in the United States, with glioblastoma multiforme (GBM) being one of the most aggressive and difficult subtypes to treat. Thus, the treatment of malignant glioma is a significant clinical problem for which new strategies are desperately needed. In this proposal we plan to pursue a strategy to treat malignant glioma with the potent antitumor cytokine, interferon beta (IFN2).

描述（由申请人提供）：脑肿瘤是美国癌症相关死亡的主要原因之一，多形性胶质母细胞瘤（GBM）是最具侵袭性和最难治疗的亚型之一。在本提案中，我们计划采用有效的抗肿瘤细胞因子干扰素-β（IFN-2）治疗恶性胶质瘤。I型（1/2）干扰素（IFN）长期以来被认为具有显著的多效性抗癌活性。然而，尽管在临床前模型中对多种肿瘤类型（包括神经胶质瘤）具有显著活性，但IFN在临床试验中的抗肿瘤功效令人失望。一个重要的促成因素包括通过下调凋亡途径对IFN介导的细胞死亡产生抗性。我们已经确定，核因子kB（NFkB）促进细胞存活，并抑制IFN靶基因的一个子集的表达，这些基因可能是IFN的抗肿瘤活性的效应子。不幸的是，NFkB不仅在包括胶质瘤在内的许多癌症中具有组成性活性，而且还可以被IFN本身激活。这一发现表明IFN的有效抗癌活性可能被NFkB活性抵消。基于这些观察，我们假设选择性抑制NF κ B将增强IFN的抗癌活性。我们将进行一个系统的和详细的评估NFkB的作用，在调节肿瘤细胞中的IFN 2的抗癌作用。基于所获得的见解，我们将选择和测试应提供协同抗肿瘤活性与IFN的补充剂。在体外证实这些药物的协同作用后，我们将在恶性胶质瘤的相关临床前模型中测试包括IFN在内的联合治疗的有效性。本项目的首要目标是通过更好地理解IFN 2对胶质瘤的作用机制和对抗它的因素来增加IFN的抗肿瘤活性。在具体目标1中，我们将研究NFkB在抑制IFN 2在胶质瘤中的抗癌活性中的作用。为了测试这一点，我们将在神经胶质瘤细胞系中确定1）经典NF：B途径对组成型和IFN诱导的NF：B活性的贡献; 2）替代NF：B途径对组成型和IFN诱导的NF：B活性的贡献;和3）药理学和遗传学NF：B抑制剂对IFN活性的影响。基于这些发现，我们将测试临床上可用的NFkB抑制剂对IFN的抗癌活性的影响，在相关的，临床前啮齿动物模型的恶性胶质瘤。在具体目标2中，我们将表征NFkB在调节IFN靶基因中的作用以及这些靶基因在IFN 2在胶质瘤中的抗癌作用中的作用。为了测试这一点，我们将：1）表征这些基因响应IFN的诱导; 2）确定它们在体外和体内影响IFN的抗癌活性中的重要性和3）通过在恶性胶质瘤的相关临床前模型中测试适当选择的组合疗法的功效来转化这些发现。公共卫生相关性：在美国，脑肿瘤是癌症相关死亡的主要原因之一，多形性胶质母细胞瘤（GBM）是最具侵袭性和最难治疗的亚型之一。因此，恶性胶质瘤的治疗是一个重要的临床问题，迫切需要新的策略。在这项提案中，我们计划采用一种有效的抗肿瘤细胞因子干扰素β（IFN 2）治疗恶性胶质瘤的策略。