Susan G Komen  
I've Been Diagnosed With Breast Cancer Someone I Know Was Diagnosed Share Your Story Join Us And Stay Informed Donate To End Breast Cancer
    Home > Research & Grants > Grants Program > Research Grants > Research Grants Awarded > Abstract

    Research Grants Awarded

    Targeting Breast Cancer at the Level of Translation Control

    Study Section:
    Tumor Cell Biology IV

    Scientific Abstract:
    Background. We have developed the first experimental treatment targeting a translation phenotype in cancerous cells to enter clinical investigation. The oncolytic poliovirus recombinant PVS-RIPO is based on cell type-specific translation in cancer cells via a heterologous rhinovirus internal ribosomal entry site (IRES). Cancer cells ectopically expressing the poliovirus receptor CD155 are susceptible to intracellular propagation and swift killing by PVS-RIPO. Clinical-grade PVS-RIPO has been manufactured at the NCI and a pre-IND meeting with the FDA is scheduled for October ‘05. Clinical trials with PVS-RIPO against recurrent primary CNS tumors are planned for late 2006. We established previously that CD155 is expressed abundantly in ~50-60% of breast cancers, which are highly susceptible to PVS-RIPO oncolysis. Therefore, clinical studies with PVS-RIPO should extend to patients with CNS complications of breast cancer. We will provide the scientific rationale and pre-clinical data to support such studies. Objective/Hypothesis. What is the mechanism of IRES-mediated alternative translation initiation in cancer? What are the molecular determinants for efficient PVS-RIPO oncolysis in breast cancer cells? Is PVS-RIPO treatment of intracerebral breast cancer xenografts in experimental animals efficacious? Specific Aims. I. Molecular mechanism of breast cancer-specific gene expression mediated by internal ribosomal entry. II. Pre-clinical efficacy studies of the oncolytic agent PVS-RIPO in breast cancer tissue culture and in experimental animals. Study Design. We will use established techniques to investigate the molecular mechanism of translation initiation at viral and cellular IRES elements in breast cancer cells, i.e. in vitro translation, protein:RNA interaction assays, ribosomal profiling. Our pre-clinical investigations will include tissue culture-based tests, analyses of breast cancer tissues as well as studies in experimental animals. Potential Outcomes and Benefits of the Research. Our research aims to decipher the molecular mechanisms governing alternative translation initiation in breast cancer cells. We will determine the specific conditions that render breast cancer cells susceptible to the investigational agent PVS-RIPO. This will lay the foundation for pre-clinical animal studies and, ultimately, clinical studies in breast cancer patients. Our research will make our highly innovative approach applicable against the disabling and invariably fatal CNS complications of breast cancer.

    Lay Abstract:
    Background. We have developed a new cancer treatment exploiting abnormal conditions for alternative gene expression via a viral genetic element, the internal ribosomal entry site (IRES), in breast cancer cells. Our approach is based on a genetically modified poliovirus, PVS-RIPO, which selectively grows within and kills breast cancer cells without causing harm to normal tissues. Cancer cells abnormally expressing the poliovirus receptor CD155 on their surface are susceptible to swift killing by PVS-RIPO. Clinical-grade PVS-RIPO has been manufactured at the National Cancer Institute, a pre-IND meeting with the FDA is scheduled for October ’05 and clinical trials against malignant glioma will begin in late 2006. We established previously that CD155 is expressed abundantly in ~50-60% of breast cancers, which are highly susceptible to PVS-RIPO killing. Therefore, clinical studies with PVS-RIPO should extend to patients diagnosed with breast cancer brain metastasis. We will provide the scientific rationale and pre-clinical data to support such studies. Objective/Hypothesis. What is the molecular mechanism of IRES-mediated alternative gene expression in cancer? What are the molecular determinants of efficient PVS-RIPO breast cancer cell killing? Is PVS-RIPO treatment of breast cancer brain metastasis in experimental animals efficacious? Specific Aims. I. Molecular mechanism of breast cancer-specific gene expression mediated by internal ribosomal entry. II. Pre-clinical efficacy studies of the oncolytic agent PVS-RIPO in breast cancer tissue culture and in experimental animals. Study Design. We will use established techniques to investigate the molecular mechanisms of gene expression at viral and cellular IRES elements in breast cancer cells, i.e. in vitro translation, protein:RNA interaction assays, ribosomal profiling. Our pre-clinical investigations include tissue culture-based and experimental animal tests. Potential Outcomes and Benefits of the Research. Our research aims to decipher the mechanisms governing IRES-mediated gene expression in breast cancer. We will determine the specific conditions that render breast cancer cells susceptible to the investigational agent PVS-RIPO. This will lay the foundation for pre-clinical animal studies and, ultimately, clinical studies in breast cancer patients. Our research will make our highly innovative approach applicable against the disabling and invariably fatal complications of breast cancer brain metastasis.