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New PET Reporter Probes for Imaging HSV-tk Gene Expression in Breast Cancer
Background: The early detection with advanced imaging technology and improved therapies with fewer side effects may help to decrease the overall death rate of breast cancer. Gene therapy clinical trails using viral and non-viral vectors have shown significant potential in treating breast cancer. Among these trails, the use of virally delivered herpes simplex virus thymidine kinase (HSV-tk) gene has attracted much attention, which provides a target for the development of reporter probes for biomedical imaging technique positron emission tomography (PET) to image HSV-tk gene expression. Fluorine-18 labeled PET reporter probes have been intensively investigated, however, carbon-11 labeled PET reporter probes are still not reported. Objective/Hypothesis: The objective is to develop a non-invasive methodology for studying, detecting and monitoring of breast cancer utilizing PET imaging technique with novel carbon-11 reporter probes that target HSV-tk gene in breast cancer gene expression and gene therapy. The hypothesis is that radiolabeled ganciclovir and penciclovir analogs labeled with positron emitting radionuclide carbon-11 may enable non-invasive monitoring of HSV-tk reporter gene expression in vivo and breast cancer response to gene transfer technology treatment using PET imaging techniques. Specific Aims: 1) to develop new reporter probes [11C]MeOGCV and [11C]MeOPCV; 2) to develop new reporter probe [11C]ABE; 3) to perform biodistribution studies with these new reporter probes in breast cancer animal models; and 4) to perform micro-PET imaging studies of HSV-tk gene expression using a high resolution/high sensitivity animal PET scanner with these new reporter probes in breast cancer animal models. Study Design: We have created a general methodology for research and development of tumor imaging agents, which includes chemistry and biological evaluation. Based on this methodology, aims 1 and 2 will use synthetic organic chemistry and PET radiochemistry for the synthesis and in vitro evaluation of new reporter probes, carbon-11 labeled nucleoside analogues; aims 3 and 4 will focus on the in vivo biological studies including biodistribution and micro-PET imaging studies of new reporter probes in breast cancer animal models. Potential Outcomes and Benefits of the Research: This novel imaging approach will have great value and special usefulness in the studying, detecting and monitoring breast cancer gene expression and gene therapy.
Breast cancer is the most common cancer among the women and the second leading cause of cancer death in women, accounting for >40,000 deaths each year in United States women. The principal cause of mortality is the development of the metastasis; early breast cancer can be cured. The early detection with advanced imaging technology such as positron emission tomography (PET) and improved therapies with fewer side effects such as gene therapy with the herpes simplex virus thymidine kinase (HSV-tk) gene may help to decrease the overall death rate of breast cancer. Novel strategies are urgently required. PET has the adventage of a being sensitive technique for imaging of breast cancer. We propose to develop a non-invasive methodology for studing, detecting and monitoring breast cancer gene expression and gene therapy utilizing PET with novel radiopharmaceuticals that target HSV-tk gene. We hypothesize that novel radiopharmaceuticals may enable non-invasive monitoring of HSV-tk gene expression in vivo and breast cancer response to gene transfer technology treatment using PET imaging techniques. We will develop carbon-11 radiolabeled antiviral nucleoside analogues as new PET HSV-tk gene reporter probes. Synthetic organic chemistry and PET radiochemistry will be used in the synthesis and radiolabeling of the gene medical probes. The breast cancer tumor models we will use are the human breast cancer/athymic mouse xenograft models implanted with several human breast cancer cell lines transduced with retroviral vector containing HSV-tk gene. Biodistribution studies will be conducted to determine the localization of the gene reporter probes in breast cancer animal models. Micro-PET imaging studies using animal PET scanner with the gene reporter probes will be performed to locate the sites of tumor growth, identify any tumor recurrence, track the HSV-tk gene, and investigate the tumor response to gene therapy. The first part will develop new HSV-tk gene reporter probes, and the second part will develop new imaging devices using an animal PET imaging system and new reporter probes. Success of the project could lead to a more refined clinical trial of gene therapy, with the knowledge about the efficiency of gene transfer and the distribution and dynamic of gene expression from PET imaging technology. This project will lay the foundation for PET imaging techniques to study HSV-tk gene in breast cancer gene therapy in human.