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. 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 noninvasive gene transfer imaging techniques. To address this hypothesis, we propose: 1) to determine the biodistribution and spectrum of toxicities associated with, and the imaging capabilities of an advanced generation adenoviral vector that is genetically modified to augment tumor tropism and to encode both a therapeutic gene and a receptor for gene transfer imaging when administered IP in animal models; 2) to determine the maximum tolerated dose, spectrum of toxicities, and antitumor activity of this novel gene therapeutic when administered IP in patients with recurrent ovarian cancer; 3) to assess the ability of this novel gene therapeutic to transfect target tumor cells in situ, to be imaged with nuclear scanning, and to elicit a host immune response when administered IP in patients with recurrent ovarian cancer; and 4) to enhance the antitumor activity of this novel therapeutic by incorporation of additional ovarian specific targeting peptides in the adenoviral vector and by using a bifunctional radiolabeled peptide. The aggregate of these studies will overcome the obstacles that are currently preventing gene therapy from reaching its potential as a new therapeutic paradigm for patients with ovarian cancer.
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