Development of aptamer-based detection and therapy strategies for ovarian cancer

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DESCRIPTION (provided by applicant): The need persists for better early detection of ovarian cancer. Currently, detection of ovarian cancer relies in part on the recognition of the tumor marker protein CA125 by antibody molecules. CA125 is the most widely assayed and best validated biomarker of ovarian cancer, but because available assays lack sufficient sensitivity and specificity, CA125 is not currently recommended for screening in the general population. More informative assays will result from the simultaneous detection of multiple cancer biomarkers, including those whose biological abundance complements CA125. Mesothelin and human epididymis protein 4 (HE4) are two relatively new biomarkers that may complement CA125 in serum tests. Currently, most assays for ovarian cancer markers rely on antibody molecules for selective recognition. Antibodies are limited in terms of their stability, reusability, and ability to be modified with imaging labels or immobilization tags. Assays incorporating aptamers (functional nucleic acid ligands) are an attractive alternative to antibody-based techniques. Aptamers are robust, easily labeled, and prepared entirely in vitro. In previous studies, some aptamers have been shown surpass antibodies in affinity for their target, which may translate into improved detection methods for cancer markers in serum tests. An additional application in which aptamers may replace antibodies is in targeting metal nanoparticle imaging agents or therapeutic payloads directly to surfaces of ovarian cancer cells. Such cell targeting may be useful for imaging the distribution of biomarkers on ovarian tumors and may enable localized cell killing by hyperthermia, reducing the need for systemic chemotherapy. The research plan proposed here aims to develop aptamers for three important ovarian cancer biomarkers. Assays that use these aptamers in conjunction with sensitive instrumental methods will then be developed. We will also perform proof-of-principle experiments in which aptamer-functionalized nanoparticles mediate high-resolution imaging and targeted hyperthermia. Public health will be positively impacted by the development of new CA125 assays to improve cancer screening and by innovative approaches to tumor cell eradication. The PI will conduct the metal nanoparticle assays during a one-year research sabbatical hosted at the University of Wisconsin Medical School (Year 1). Two additional years of support are requested during which the PI, back at her home institution of Oberlin College, will train two undergraduate students per year and mentor them in aptamer selection and assay development. A recently graduated Oberlin undergraduate will be employed as a full-time research technician in Year 3.