Targeting Translation Control in Malignant Glioma

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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.