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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-N (02))
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Arya, Suresh
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Duke University
Schools of Medicine
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Desjardins, Annick; Gromeier, Matthias; Herndon 2nd, James E et al. (2018) Recurrent Glioblastoma Treated with Recombinant Poliovirus. N Engl J Med 379:150-161
Gromeier, Matthias; Nair, Smita K (2018) Recombinant Poliovirus for Cancer Immunotherapy. Annu Rev Med 69:289-299
Bryant, Jeffrey D; Brown, Michael C; Dobrikov, Mikhail I et al. (2018) Regulation of Hypoxia-Inducible Factor 1? during Hypoxia by DAP5-Induced Translation of PHD2. Mol Cell Biol 38:
Thompson, Eric M; Brown, Michael; Dobrikova, Elena et al. (2018) Poliovirus Receptor (CD155) Expression in Pediatric Brain Tumors Mediates Oncolysis of Medulloblastoma and Pleomorphic Xanthoastrocytoma. J Neuropathol Exp Neurol 77:696-702
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Brown, Michael C; Holl, Eda K; Boczkowski, David et al. (2017) Cancer immunotherapy with recombinant poliovirus induces IFN-dominant activation of dendritic cells and tumor antigen-specific CTLs. Sci Transl Med 9:
Brown, Michael C; Gromeier, Matthias (2017) MNK Controls mTORC1:Substrate Association through Regulation of TELO2 Binding with mTORC1. Cell Rep 18:1444-1457
Chandramohan, Vidyalakshmi; Bryant, Jeffrey D; Piao, Hailan et al. (2017) Validation of an Immunohistochemistry Assay for Detection of CD155, the Poliovirus Receptor, in Malignant Gliomas. Arch Pathol Lab Med 141:1697-1704
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

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