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    Therapy of Breast Cancer CNS Metastasis with Oncolytic Polioviruses

    Scientific Abstract:
    Therapy of Breast Cancer CNS Metastasis with Oncolytic Polioviruses The incidence of CNS metastasis from primary breast carcinoma is on the rise. Since current treatment options are inadequate and the outcome is usually fatal, novel therapeutic strategies are needed to combat CNS complications of breast cancer. We have developed a novel approach towards the treatment of CNS malignancies based on non-pathogenic poliovirus recombinants. Replacing the poliovirus internal ribosomal entry site (IRES) with its counterpart from human rhinovirus type 2 (HRV2) yielded the chimera PVS-RIPO. The IRES substitution ablated growth of PVS-RIPO in neuronal cells but did not affect its lytic potential in tumor cells. Tumor selective replication, as well as the up-regulated expression of poliovirus receptor CD155 in many tumor cells, allows PVS-RIPO to selectively target neoplastic cells without exhibiting the neurovirulence of wild-type poliovirus. PVS-RIPO has undergone thorough neurovirulence testing in non-human primates at the Food and Drug Administration and was found to be non-pathogenic after intraspinal inoculation. It is currently being prepared for phase-I clinical trials against glioblastoma multiforme at the National Cancer Institute. Since oncolytic poliovirus recombinants are ideally suited for therapeutic approaches against neoplasms arising in the CNS, we are investigating their use against CNS metastasis secondary to systemic cancer. As breast cancer accounts for a significant proportion of cases of neoplastic meningitis and brain metastasis, we are exploring the therapeutic potential of PVS-RIPO against breast cancer in the CNS. In preliminary studies in athymic rats and tissue cultures, PVS-RIPO has proven to be highly effective against breast cancer cells and xenografts inoculated intracerebrally and intrathecally. Susceptibility of breast cancer cells towards PVS-RIPO is mediated by expression of the poliovirus receptor CD155 and permissiveness for HRV2 IRES function. Our project aims to elucidate the molecular principles underlying tumor specificity and explore the therapeutic potential of oncolytic poliovirus recombinants against metastatic breast cancer.

    Lay Abstract:
    Therapy of Breast Cancer CNS Metastasis with Oncolytic Polioviruses Breast cancer is frequently complicated by metastasis to the brain, a condition poorly responsive to available treatment options. We have developed a novel treatment strategy based on poliovirus for cancers arising in the central nervous system. Through genetic manipulation of poliovirus we produced an artificial infectious agent that selectively destroys cancerous cells while failing to grow in normal cells. This remarkable property was achieved by splicing a small portion of genetic information from rhinovirus, a common-cold causing virus related to poliovirus, into the poliovirus genome. The agent, named PVS-RIPO, has passed safety evaluation at the Food and Drug Administration and is currently being produced by the National Cancer Institute for clinical trials against primary brain tumors. Our project aims to exploit the proven benefits of PVS-RIPO against primary brain tumors to treat brain metastasis secondary to breast cancer. We have already demonstrated that PVS-RIPO efficiently destroys breast cancer cell lines and is highly effective against metastatic breast cancer in two rat models. We plan to expand our studies to systematically test breast cancer cell lines and breast cancer tissues obtained from patients for susceptibility to PVS-RIPO. Furthermore, we will carry out analyses to identify the molecular mechanisms that are responsible for the selective destruction of tumor cells without concomitant damage to the normal human organism. Given the imminent introduction of PVS-RIPO as a novel treatment option for malignant brain tumors, our studies would provide a strong rationale to make this agent available for the treatment of metastatic breast cancer as well.