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).

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA133322-04
Application #
8212507
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Mccarthy, Susan A
Project Start
2009-03-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
4
Fiscal Year
2012
Total Cost
$505,966
Indirect Cost
$94,956
Name
University of Tennessee Health Science Center
Department
Pathology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Yang, Chuan He; Yue, Junming; Pfeffer, Susan R et al. (2014) MicroRNA-21 promotes glioblastoma tumorigenesis by down-regulating insulin-like growth factor-binding protein-3 (IGFBP3). J Biol Chem 289:25079-87
Yang, Chuan He; Yue, Junming; Sims, Michelle et al. (2013) The curcumin analog EF24 targets NF-*B and miRNA-21, and has potent anticancer activity in vitro and in vivo. PLoS One 8:e71130
Fan, Meiyun; Krutilina, Raisa; Sun, Jing et al. (2013) Comprehensive analysis of microRNA (miRNA) targets in breast cancer cells. J Biol Chem 288:27480-93
Garner, Jo Meagan; Fan, Meiyun; Yang, Chuan He et al. (2013) Constitutive activation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor *B signaling in glioblastoma cancer stem cells regulates the Notch pathway. J Biol Chem 288:26167-76
Orr, W Shannon; Denbo, Jason W; Saab, Karim R et al. (2013) Curcumin potentiates rhabdomyosarcoma radiosensitivity by suppressing NF-?B activity. PLoS One 8:e51309
Niu, Jixiao; Shi, Yuling; Tan, Guangyun et al. (2012) DNA damage induces NF-ýýB-dependent microRNA-21 up-regulation and promotes breast cancer cell invasion. J Biol Chem 287:21783-95
Li, Kui; Li, Nan L; Wei, Dahai et al. (2012) Activation of chemokine and inflammatory cytokine response in hepatitis C virus-infected hepatocytes depends on Toll-like receptor 3 sensing of hepatitis C virus double-stranded RNA intermediates. Hepatology 55:666-75
Orr, Wayne S; Denbo, Jason W; Saab, Karim R et al. (2012) Liposome-encapsulated curcumin suppresses neuroblastoma growth through nuclear factor-kappa B inhibition. Surgery 151:736-44
Janjetovic, Z; Brozyna, A A; Tuckey, R C et al. (2011) High basal NF-ýýB activity in nonpigmented melanoma cells is associated with an enhanced sensitivity to vitamin D3 derivatives. Br J Cancer 105:1874-84
Yang, Chuan He; Yue, Junming; Pfeffer, Susan R et al. (2011) MicroRNA miR-21 regulates the metastatic behavior of B16 melanoma cells. J Biol Chem 286:39172-8

Showing the most recent 10 out of 15 publications