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 eIF4G?s 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.
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.
|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|
|Walton, Ross W; Brown, Michael C; Sacco, Matthew T et al. (2018) Engineered Oncolytic Poliovirus PVSRIPO Subverts MDA5-Dependent Innate Immune Responses in Cancer Cells. J Virol 92:|
|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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