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Devlopment of Breast Cancer Targeting Gene Therapy Vectors
An ideal breast cancer diagnostic or therapeutic agent would specifically target malignant cells to identify or treat these cells while avoiding normal tissues. To achieve targeted diagnostic and therapeutic agents, cell-targeting ligands need to be identified that can breast cancer cells in vivo. While a number of technologies can now generate millions of potential cell-targeting agents, preclinical testing of these ligands and agents is fundamentally limited by a lack of high throughput, quantitative methods that are suited to the research laboratory environment. Given these issues, this project will develop ligand discovery and tomographic imaging technologies to screen and test cell-targeting agents in small animals. To achieve this goal, this project will combine two very different research groups: one specializing in cell-targeting and gene therapy and the second group specializing in tomographic imaging technologies. These technologies will be validated in mouse xenograft models of human breast cancer. This work will be pursued in the following Aims:
Specific Aim 1. Identify Breast Cancer Targeting Ligands Using Improved Peptide Libraries.
Specific Aim 2. Apply a Tomographic Fluorescence And Luminescence Imager To Quantitatively Analyze The Distribution Of Ligands, Vectors, And Gene Delivery In Vivo In Small Animals.
Specific Aim 3. Evaluate Cell-targeting Ligand and Gene Therapy Vector Performance In Vivo Using Tomographic Fluorescence and Luminescence Imaging.
Successful pursuit of this project will identify and apply breast cancer targeting ligands for diagnostic and drug and gene therapy applications. This project will also test the utility of tomographic imaging technologies to screen potential ligands. As such, this project holds promise for opening the preclincal research bottleneck that effectively chokes the pipeline between ligand discovery and their ultimate use in humans for diagnostic and therapeutic applications. Beyond developing these imaging technologies, this project will also test candidate cell-targeting ligands and gene therapy vectors for human breast cancer to move these reagents closer to clinical application.
The inability to identify and effectively treat metastatic breast cancer is due in part to an inability to deliver diagnostic agents, drugs, and gene therapies directly to cancer cells throughout the body. This lack of direct delivery means that too little of each agent arrives at tumor cells to identify or kill them. Worse yet, the lack of specificity also means that too much of the drug or gene goes to normal cells like those in the bone marrow, and this non-specific killing is the source of many of the complications and pain associated with current cancer therapies. Given these fundamental problems in cancer diagnostics and therapy, this project will attempt to circumvent the lack of specificity of agents by creating novel molecules that can find and bind specifically to breast cancer cells. These "targeting" molecules will then be used in state of the art therapeutic agents involving gene therapy to attempt to deliver genes specifically to human breast cancer cells in mice. If successful, this project will lay the groundwork for future clinical applications to diagnose and treat primary and advanced metastatic breast cancer in which these "smart" targeting agents will hunt down primary and metastatic tumor cells throughout the body to more effectively identify and control advanced breast cancer in women.