) Defining new therapeutic paradigms for patients with ovarian cancer is of critical importance, given that this is a uniformly fatal disease for the vast majority of women afflicted by it. Many human cancers, including ovarian cancer, are now recognized to be the result of accumulated genetic events, which culminate in the transformed malignant phenotype. Therefore, it is rational to investigate the utility of various gene therapy strategies as a means to improve clinical outcome. Of note, distinct gene therapeutic initiatives have been rapidly translated into clinical trials for ovarian cancer, several of which have been conducted by the investigators of this proposal. The implementation of these trials, however, has revealed limitations that relate primarily to the inadequacy of current vector systems to achieve efficient and specific tumor cell targeting and to the logistics and morbidity associated with invasive assessment of in vivo gene transfer. It is our hypothesis that the therapeutic utility of cancer gene therapy approaches for ovarian cancer will be substantially improved by the employment of a new generation of vector systems capable of efficient and tumor cell-specific transduction and by the application of novel non-invasive gene transfer imaging techniques. To address this hypothesis, we propose: (1) to develop and validate a genetically modified adenovirus that augments tumor targeting and achieves an enhanced anti-tumor effect in the context of ovarian cancer, (2) to develop and validate, in the context of ovarian cancer, a gene transfer imaging methodology based on radionuclide imaging of genetically transferred receptors, (3) to prepare a Good Manufacturing Practice (GMP) adenoviral vector for a human clinical gene therapy trial in the context of ovary cancer that is genetically modified to augment tumor tropism and that encodes both a therapeutic gene and a receptor for gene transfer imaging, and (4) to conduct a phase I/II trial in the context of ovary cancer utilizing a GMP adenoviral vector that is genetically modified to augment tumor tropism and that encodes both a therapeutic gene and a receptor for gene transfer imaging. Success in these endeavors will overcome the obstacles that are currently preventing gene therapy from reaching its potential as a clinically relevant option for ovarian cancer. Pursuant to this SPORE application, completion of these objectives will allow for establishment of gene therapy as a novel and effective treatment paradigm for ovarian cancer.
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