Novel Ovarian Cancer Detection Agents from Phage Display

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DESCRIPTION (provided by applicant): Ovarian adenocarcinomas are the largest class of gynecologic malignancies in the United States with respect to incidence and mortality. While treatable in their earliest stage, advanced or metastatic forms of ovarian cancer are usually deadly. Because ovarian cancer is often asymptomatic in its early stages, ~70% of patients have advanced or metastatic disease at time of diagnosis. Current screening methods include ultrasonography, pelvic exam, and serum screening for CA125. Unfortunately, these tests are not specific for ovarian cancer and invasive surgical biopsy is required for proper diagnosis. Improved early diagnosis and therapy will result from a more directed approach in which antigens specific to or overexpressed on ovarian tumor cells are targeted. New peptide-based molecular probes to facilitate cancer detection and imaging are rapidly evolving due to implementation of bacteriophage (phage) display approaches. We previously developed novel in vivo phage display screening techniques to identify peptides that target numerous types of cancers including those of the breast and prostate. However, it was observed that the majority of the synthesized peptides identified by phage display, while exhibiting excellent in vitro binding properties, failed to image tumors in living animals. It has been our experience that synthetic peptides, which were successful imaging agents, were derived from phage that had demonstrated in vivo tumor target properties. Here, it is hypothesized that phage selected in vivo, in human ovarian tumor-bearing mice, once fluorescently labeled, can be easily re-screened in vivo for tumor-homing propensity, thus streamlining the process of development of peptide-based ovarian cancer imaging and therapeutic agents. Radiolabeled versions of the identified peptides will be examined for their ability to image ovarian tumors in mice using Single Photon Emission Computed Tomography (SPECT). In this proposal, our expertise in phage display, oncology, imaging, and peptide radiochemistry will be integrated to provide novel tumor antigen-specific phage particles and peptides for ovarian cancer detection. Innovative in vivo phage screens are proposed to expedite the process of discovery of new peptide-based tumor imaging agents. A long-term goal of this work is to translate the radiolabled peptides into the clinic for the non-invasive screening and detection of ovarian cancer. Specifically we propose to obtain new classes of ovarian cancer targeting peptides by performing in vivo phage display selections in human ovarian carcinoma-bearing mice. Second, phage selected from the screens will be fluorescently labeled and employed in in vivo optical imaging screens to expedite discovery of new ovarian tumor imaging agents. Last, peptides corresponding to phage with optimal in vivo imaging properties will be synthesized and radiolabled with 111In and 99mTc and examined for their SPECT imaging efficacy in vivo. Novel phage display and peptide radiochemistry approaches are described to advance the detection of ovarian cancer a cancer that deserves much more research and attention. PUBLIC HEALTH RELEVANCE The discovery and implementation of novel ovarian selective tumor targeting agents has the potential to improve diagnostic efficacy and impact disease treatment thus improving patient comes and replacing highly invasive procedures with minimally invasive ovarian diagnostic agents.