The ability of tumors to develop a blood supply is critical to their capacity for sustained growth and their spread to distant organs. This process of new vessel development, termed angiogenesis, is the result of a complex series of interactions between the tumor and the host. The endothelial cell is the main focus of this process, however, there are a number of other cell types that play a critical role. Our laboratory is focused on understanding the process of tumor angiogenesis with the goal of developing therapies which target the tumor vasculature. To achieve this goal we have embarked on several lines of investigation. These include: 1. the development and validation of in vitro and in vivo model systems for studying tumor-blood vessel-host interactions, 2. the use of gene expression profiling to better elucidate the changes in endothelial cell function in the tumor environment, 3. the study of gene therapy techniques to more efficently deliver anti-angiogenic agents to target tumor tissue, and 4. the translation of these findings to clinical protocols which apply these novel anti-angiogenic therapies to the treatment of patients with cancer. With respect to our model systems, we have developed and continue to utilize a variety of in vitro and in vivo assay systems. Cell proliferation and migration assays help us to understand the direct effects of agents on endothelial cell function. Ex-vivo rat aortic as well as human saphenous vein (developed in our laboratory in collaboration with William Figg) ring assays allow us to examine the process of neovessel formation in a controlled setting. A variety of in vivo assays such as the CAM assay, subcutanoeus matrigel and corneal micropocket assays help us to study the contribution of other host cells to the process of angiogenesis. We also rely on a variety of mouse tumor models including transplantable and spontaneously occurring transgenic models of cancer. Our laboratory has also developed imaging systems using MRI, PET and Fluorescent imaging to stduy changes in tumor blood flow in response to ant-angiogenic therapies. Using cDNA microarray technology, we have begun to identify specific pathways involved in the response of endothelium to tumor derived factors as well as exogenously administered antiangiogenic agents. We have devised strategies to study the endothelial cell specifically in a variety of tissue ranging from normal to neoplastic. Using the techniques of laser capture microdissection (LCM), antibody-bead selection and RNA amplification we have successfully studied endothelial cells isolated from responding and non-responding tumor tissue after exposure to anti-angiogenic agents. Utilizing this approach, we hope to identify novel targets for therapy. As a result of our use of the aforementioned models, we have studied gene therapy techniques as a means to deliver anti-angiogenic agents in vivo. The potential pharmacokinetic, biotechnological, and economic drawbacks of chronic delivery of recombinant anti-angiogenic proteins have led investigators to address the feasibility of delivering antiangiogenic agents by means of gene therapy. Two general strategies for the antiangiogenic gene therapy of cancer have been proposed: tumor-directed gene therapy and systemic gene therapy. Traditionally, the goal of cancer gene therapy has been to select gene delivery vectors which selectively target tumor tissue with transgenes that produce toxic gene products, enhance tumor immunogenicity, or specifically increase the tumor's susceptibility to chemotherapeutics, radiation, or biologic agents. Along these lines, others have advocated tumor-directed antiangiogenic gene therapy to increase local concentrations of antiangiogenic agents within the tumor, in order to achieve an antitumor effect without the risk of systemic toxicity. To date, however, toxicity of recombinant forms of endogenous anti-angiogenic agents has not been demonstrated, although some synthetic anti-angiogenic agents have been associated with toxicity in preclinical models. Because of this apparent lack of toxicity of antiangiogenic agents, a systemic approach to antiangiogenic gene therapy is a strategy we have pursued. The goal of this strategy would be to utilize the patient's normal tissues as a """"""""factory"""""""" for the production of increased circulating levels of an antiangiogenic agent. This approach may allow the development and use of more efficient gene delivery systems which otherwise would be inappropriate for tumor-directed cytotoxic (""""""""suicide"""""""") gene therapy. In addition, the effectiveness of tumor-directed gene therapy may be limited by the requirement for an established tumor blood supply to deliver the vector, which might limit efficacy against micrometastatic disease in a prevascular stage of growth. A further understanding of the role of various pro- and antiangiogenic factors in various stages of tumor development may help tailor gene therapy strategies and specific antiangiogenic genes to a given clinical scenario. To accomplish this we have studied a variety of genes encoding antiangiogenic agents such as, endostatin, canstatin, TIMP2, EMAP-II, IP-10, PEDF, IL-18 and IL-12. We have made use of vectors such as adenovirus, retrovirus, vaccinia virus and liposomes. The ultimate use of anti-angiogenic agents to treat cancer in patients may be as adjuvant therapies to other modalities such as surgery. In order to explore their use as adjuvants, we have developed a variety of models systems as well as intiated a clinical trial. We are currently studying the use of the oral anti-angiogenic agent thalidomide as an adjuvant therapy following the resection of colon cancer metastases in patients. We are also utilizing dynamic MRI and PET scanning to study the effects of a variety of anti-angiogenic agents currently being used in clinical trials. Our goal is to use the information we gather from the studies outlined above to help reduce the burden of cancer in our patients.
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