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.
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).
|Pfeffer, Susan R; Fan, Meiyun; Du, Ziyun et al. (2017) Unphosphorylated STAT3 regulates the antiproliferative, antiviral, and gene-inducing actions of type I interferons. Biochem Biophys Res Commun 490:739-745|
|Yang, Chuan He; Wang, Yinan; Sims, Michelle et al. (2017) MicroRNA203a suppresses glioma tumorigenesis through an ATM-dependent interferon response pathway. Oncotarget 8:112980-112991|
|Wang, Ruishan; Davidoff, Andrew M; Pfeffer, Lawrence M (2016) Bortezomib sensitizes human glioblastoma cells to induction of apoptosis by type I interferons through NOXA expression and Mcl-1 cleavage. Biochem Biophys Res Commun 478:128-134|
|Yang, Chuan He; Wang, Yinan; Sims, Michelle et al. (2016) MiRNA203 suppresses the expression of protumorigenic STAT1 in glioblastoma to inhibit tumorigenesis. Oncotarget 7:84017-84029|
|Sethuraman, Aarti; Brown, Martin; Seagroves, Tiffany N et al. (2016) SMARCE1 regulates metastatic potential of breast cancer cells through the HIF1A/PTK2 pathway. Breast Cancer Res 18:81|
|Wu, Zhao-Hui; Pfeffer, Lawrence M (2016) MicroRNA regulation of F-box proteins and its role in cancer. Semin Cancer Biol 36:80-7|
|Garner, Jo Meagan; Ellison, David W; Finkelstein, David et al. (2015) Molecular heterogeneity in a patient-derived glioblastoma xenoline is regulated by different cancer stem cell populations. PLoS One 10:e0125838|
|Pfeffer, Susan R; Yang, Chuan He; Pfeffer, Lawrence M (2015) The Role of miR-21 in Cancer. Drug Dev Res 76:270-7|
|Zhao, Guannan; Guo, Yuqi; Chen, Zixuan et al. (2015) miR-203 Functions as a Tumor Suppressor by Inhibiting Epithelial to Mesenchymal Transition in Ovarian Cancer. J Cancer Sci Ther 7:34-43|
|Yang, Chuan He; Pfeffer, Susan R; Sims, Michelle et al. (2015) The oncogenic microRNA-21 inhibits the tumor suppressive activity of FBXO11 to promote tumorigenesis. J Biol Chem 290:6037-46|
Showing the most recent 10 out of 33 publications