Once epithelial neoplasms such as carcinomas of the breast and prostate become metastatic and develop resistance to hormonal therapy and chemotherapy, there are no effective options for the control of the disease. As a novel approach to treat these and other malignancies, we constructed a fusion protein called an Icon, composed of factor VII (fVII) as the targeting domain and the Fc region of IgG as the effector domain that activates a cytolytic immune attack against cells that bind the Icon. The Icon binds with exceptional affinity and specificity to tissue factor (TF), the natural receptor for fVII that is expressed on endothelial cells of the vasculature in all solid tumors but not in normal tissues. TF also is expressed on malignant tumor cells, providing a target for both the tumor vasculature and tumor cells. Previous data in a human tumor xenograft model showed that intratumoral injections of an adenoviral vector encoding the Icon can induce regressions of the injected tumor as well as tumors elsewhere in the body that were not injected. We now propose the following specific aims which take advantage of the projects and cores of the Vascular Therapy Program Project Grant in order to further prepare the Icon for cancer treatment.
Specific Aim # 1: Use of intravital microscopy to optimize the dose, schedule and optimal mode of delivery of the icon for therapy: intratumoral injection of the Icon vector vs tail vein injection of the Icon protein (intravital microscopy provides short term data on the selectivity of binding of the Icon to tumor vasculature and response of the tumor vascular endothelial cells as well as the tumor cells);
Specific Aim #2 : Use of the human tumor xenograft model for the optimization of the dose, schedule and optimal mode of delivery of the Icon for therapy: intratumoral injection of the Icon vector vs tail vein injection of the Icon protein (the xenograft model provides long term tumor response data as well as information on selectivity of binding of the Icon to the tumor vasculature);
Specific Aim #3 : Use of transgenic mouse models of spontaneous cancer and human Tissue Factor to test the safety, selectivity and efficacy of the Icon for suppressing growth of established disease which has developed over months (rather than over days as is the case with the intravital microscopy and xenograph models) as well as its spread (metastasis) to other organs;
Specific Aim #4 : Study of the effect of Icon therapy combined with other tumor vascular targeting treatments on the tumor vasculature and the tumor cells as well the study of the changes which occur in the Icon after its introduction into the bloodstream before binding to TF, and the processing of the TF/fVII complex after it is formed;
and Specific Aim #5 : a Phase I clinical trial of the Icon. If these proposed studies show that the Icon is safe and effective in the neoplasms proposed for study, it may be possible to use the Icon for the many other types of cancers that depend on a neovasculature for continued growth.
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