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    Awarded Grants
    Characterization of VSV Oncolytic Activity in Breast Cancer Model Systems

    Scientific Abstract:
    Breast cancer remains the most common malignant disease in women in both the developed and developing world. Although current treatments for breast cancer (surgery, radiation, chemotherapy, and hormone therapy) have greatly reduced the mortality rate associated with the disease, they remain largely ineffective against aggressive (metastatic) forms of the disease and often produce unwanted side-effects as a result of their lack of specificity. These shortcomings have led many to begin developing alternative treatments that have potential for greater efficacy and specificity. For instance, viral vectors have been the focus of intense research in recent years because they are extremely genetically malleable and can be manipulated to deliver foreign genes to specific tissues of various origins (e.g. breast, lung, brain, etc.). One such virus, vesicular stomatitis virus (VSV), has been investigated intensely by our laboratory as a potential treatment for malignant disease. Much of this interest is based on the initial finding that VSV replicates within and efficiently kills most types of cancer cells in vitro, but has little effect on normal cells. Studies initiated as a result of these observations have revealed that VSV is also very effective at specifically eliminating solid and metastatic breast tumors in vivo. The overall goal of this research proposal is to better characterize the oncolytic activity of vesicular stomatitis virus (VSV) in a variety of breast cancer models in hopes of developing a safer and more effective treatment for breast malignancies. Specifically, the studies are aimed at elucidating the mechanism by which VSV infects and destroys breast cancer cells in both in vitro (Aim I) and in vivo (Aim II) systems. Since malignant cells often contain flaws in the innate antiviral interferon (IFN) system that render them susceptible to the destructive effects of VSV, Aim I will largely focus on this cellular pathway (e.g. IFN synthesis and signaling) and its role in VSV-mediated oncolysis. In contrast, Aim II will largely focus on the role of the host immune system in the selective destruction of solid and metastatic breast tumors following treatment with recombinant forms of VSV. In addition to providing vital clues into the mechanism of oncolysis and tumorigenesis, these analyses should allow us to generate a new series of viruses that exploit the innate and adaptive immune systems and exhibit increased safety and efficacy when used to treat breast cancer.

    Lay Abstract:
    Breast cancer remains the most common malignant disease in women in both the developed and developing world. Although current treatments for breast cancer (surgery, radiation, chemotherapy, and hormone therapy) have greatly reduced the mortality rate associated with the disease, they remain largely ineffective against aggressive (metastatic) forms of the disease and often produce unwanted side-effects as a result of their lack of specificity. These shortcomings have led many to begin developing alternative treatments that have potential for greater effectiveness and specificity. One such treatment involves using certain genetically-altered viruses to target and destroy tumor cells. Vesicular stomatitis virus (VSV) has been the focus of research in our laboratory because, unlike other viruses, it naturally infects and kills tumor cells much more efficiently than it does normal cells. This specificity occurs because normal cells, unlike cancer cells, make certain proteins (e.g. interferons) that potently inhibit VSV replication and protect the cell. Using this knowledge, we attempted to treat mouse breast tumors with normal and genetically-altered VSV constructs and found that they very effectively eliminated both solid and metastatic breast tumors, while having little effect on the surrounding normal tissue. The overall goal of this research proposal is to better characterize how VSV selectively destroys these breast cancer cells in hopes of developing a safer and more effective treatment for breast malignancies. Studies proposed in Aim I will address how VSV kills breast cancer cells that are grown in the absence of other types of cells (e.g. in plastic dishes). In particular, we would like to determine why breast cancer cells are not protected by the interferon proteins, which are mentioned above. For instance, breast cancer cells may not make the normally protective interferon proteins or they may make them, but not respond to them properly. Similarly, Aim II will focus on how VSV kills breast cancer cells when they are grown within animals. By doing these experiments, we would like to determine if the host (mouse) immune system helps the virus destroy the tumors. Taken together, we hope that the studies in Aim I and II will provide vital clues into the mechanism by which VSV selectively targets and kills breast cancer cells. Also, we hope that these analyses will allow us to generate a new series of genetically-altered viruses that have even greater effectiveness and safety when used to treat breast cancers.