Cancer cells exhibit abnormal properties, such as uninhibited growth/proliferation, invasion of surrounding tissues/metastasis and the diversion of blood supply, because normal gene expression programs preventing healthy cells from developing malignancy are deregulated. An important part of this deregulation is abnormal control of protein synthesis from messenger RNAs (mRNAs) in cancer cells. The mechanisms that provide global control of gene expression as well as translation regulation of specific mRNAs with important biological functions hold the key to understand many aspects of cancer cell biology. Most importantly, abnormal regulation of protein synthesis in malignant cells can be exploited for cancer therapy. This principle has been demonstrated with viruses genetically engineered to specifically express viral gene products in malignant glioma cells, while being unable to translate their genomes in normal brain cells. Our long-term goals are to unravel the principles of translation regulation in cancer cells and how they differ from normal cells. A better understanding of translation control in cancer will help to develop new strategies for therapeutic intervention targeting aberrant protein expression control. This proposal is designed to test several hypotheses regarding translation regulation in malignant glioma, the most common and devastating form of cancer in the brain. We will investigate three Specific Aims: 1) The role of the DRBP76:NF45 heterodimer in translation control in primary explant cultures. We will evaluate the role of an RNA-binding protein complex in the regulation of protein synthesis in patient-derived glioma cells. 2) Post-transcriptional gene regulation by the DRBP76:NF45 heterodimer in glioma vs. neuronal cells. We will employ immunoprecipitation of RNA-binding protein:mRNA complexes and genomic arrays to identify mRNAs in glioma and neuronal cells that are regulated by the DRBP76:NF45 heterodimer. 3) Herpesvirus recombinants targeting translation control in glioma. We will manipulate the herpesvirus genome to selectively drive viral gene expression in glioma cells by utilizing glioma-specific translation control elements. The knowledge obtained from our studies will be applied towards implementation of new anti-cancer approaches targeting abnormal translation regulation in malignant glioma. A prototype oncolytic poliovirus, engineered to selectively target malignant glioma cells at the level of translation control is scheduled to enter clinical investigation within the next year.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA124756-04
Application #
7745441
Study Section
Special Emphasis Panel (ZRG1-BDCN-N (02))
Program Officer
Arya, Suresh
Project Start
2007-01-17
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
4
Fiscal Year
2010
Total Cost
$266,760
Indirect Cost
Name
Duke University
Department
Genetics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Brown, Michael C; Gromeier, Matthias (2017) MNK Controls mTORC1:Substrate Association through Regulation of TELO2 Binding with mTORC1. Cell Rep 18:1444-1457
Holl, Eda K; Brown, Michael C; Boczkowski, David et al. (2016) Recombinant oncolytic poliovirus, PVSRIPO, has potent cytotoxic and innate inflammatory effects, mediating therapy in human breast and prostate cancer xenograft models. Oncotarget 7:79828-79841
Brown, Michael C; Gromeier, Matthias (2015) Oncolytic immunotherapy through tumor-specific translation and cytotoxicity of poliovirus. Discov Med 19:359-65
Brown, Michael C; Gromeier, Matthias (2015) Cytotoxic and immunogenic mechanisms of recombinant oncolytic poliovirus. Curr Opin Virol 13:81-5
Dobrikov, Mikhail I; Shveygert, Mayya; Brown, Michael C et al. (2014) Mitotic phosphorylation of eukaryotic initiation factor 4G1 (eIF4G1) at Ser1232 by Cdk1:cyclin B inhibits eIF4A helicase complex binding with RNA. Mol Cell Biol 34:439-51
Brown, Michael C; Dobrikova, Elena Y; Dobrikov, Mikhail I et al. (2014) Oncolytic polio virotherapy of cancer. Cancer 120:3277-86
Brown, Michael C; Dobrikov, Mikhail I; Gromeier, Matthias (2014) Mitogen-activated protein kinase-interacting kinase regulates mTOR/AKT signaling and controls the serine/arginine-rich protein kinase-responsive type 1 internal ribosome entry site-mediated translation and viral oncolysis. J Virol 88:13149-60
Brown, Michael C; Bryant, Jeffrey D; Dobrikova, Elena Y et al. (2014) Induction of viral, 7-methyl-guanosine cap-independent translation and oncolysis by mitogen-activated protein kinase-interacting kinase-mediated effects on the serine/arginine-rich protein kinase. J Virol 88:13135-48
Dobrikov, Mikhail I; Dobrikova, Elena Y; Gromeier, Matthias (2013) Dynamic regulation of the translation initiation helicase complex by mitogenic signal transduction to eukaryotic translation initiation factor 4G. Mol Cell Biol 33:937-46
Lawson, Sarah K; Dobrikova, Elena Y; Shveygert, Mayya et al. (2013) p38? mitogen-activated protein kinase depletion and repression of signal transduction to translation machinery by miR-124 and -128 in neurons. Mol Cell Biol 33:127-35

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