Cancer cells exhibit deregulated growth and proliferation, because they inappropriately co-opt mitogenic signaling pathways that converge on translation machinery and control ribosome recruitment to mRNAs. We are exploiting this principle to target glioblastoma (GBM) with genetically recombinant poliovirus. Conventional protein synthesis is initiated upon engaging a complex protein network at the canonical 5' cap-structure on mRNAs. Certain mRNAs encoding critical growth, proliferation and survival proteins can evade this regulatory constraint by recruiting ribosomal subunits directly, in a cap-independent manner. Intriguingly, the basic mechanism employed by such mRNAs to initiate translation is shared by poliovirus. Through genetic manipulation of poliovirus RNA sequences involved in viral translation, we eliminated viral replication capacity in the normal CNS, without affecting its strong cytotoxicity for GBM. We discovered that PVSRIPO's tumor cytotoxicity is determined by MAPK signals to translation machinery that favor cap-independent translation in malignancy. Our findings suggest that such signals to translation factors may participate in cell cycle regulation by coordinating gene expression via alternative translation initiation during mitosis. This project aims to unravel the physiological significance of cap-independent translation in cancer, to elucidate mechanisms that control its activity and to develop rational strategies to target it for cancer therapy. We propose three Specific Aims: 1) Unravel the physiological role and control of cap- independent translation initiation during mitosis. We will investigate the molecular basis for induction of cap- independent translation during mitosis. 2) Elucidate the mechanism of IRES-mediated translation controlled by eIF4G. We identified signal transduction pathways that converge on the central scaffold of the translation apparatus and ribosome adaptor, eIF4G. We will study the molecular mechanisms regulating eIF4Gs role in cap-independent translation initiation. 3) Identify strategies to enhance glioma cell killing throuh targeted induction of cap- independent translation. Inhibition of mTORC1 elicits a series of effects on translation machinery that jointly induce cap-independent translation in cancer cells. We will test combining the mTORC1 inhibitor rapamycin with oncolytic poliovirus to synergistically enhance tumor cell killing in an animal glioma model.

Public Health Relevance

Control over the synthesis of proteins is profoundly de-regulated in all cancers, due to abnormal activation of signaling pathways to the protein synthesis apparatus. We discovered an innovative strategy that exploits this fact for efficient tumor cell killing with a genetically recombinant poliovirus. This project aims to provide the scientific basis for upcoming clinical trials of our agent and elucidate basic mechanisms of de-regulated protein synthesis in cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA124756-09
Application #
8849387
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Muszynski, Karen
Project Start
2007-01-17
Project End
2016-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
9
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Duke University
Department
Surgery
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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