A novel diagnostic test for Irinotecan and Topotecan sensitivity

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DESCRIPTION (provided by applicant): The long term objective of this Phase 1 study is to produce an antibody-based diagnostic assay to detect tumor responsiveness to a widely used class of chemotherapeutic agents derived from camptothecin that includes Irinotecan and Topotecan. The assay will be based on a novel biomarker associated with cellular sensitivity to camptothecin and will have clinical application to distinguish cancer patients likely to respond to camptothecin-derived therapeutics from those unlikely to respond. With this information, the physician can tailor the treatment regimen to be better adapted to the individual patient's tumor phenotype, thereby improving the chances of successful treatment. There is an urgent and unmet need for diagnostic assays of this type for camptothecin-derived chemotherapeutic drugs because of the wide application of these drugs today in the treatment of a variety of cancers. Nevertheless, because a substantial fraction of tumors do not respond to therapy due to poorly understood resistance mechanisms, and because there are presently few diagnostic tools available to the physician to predict therapy responses, there is a significant risk that some patients will be exposed to the toxic side effects of treatment without therapeutic benefit, and will lose time that could have been used for other treatments. The Specific Aims of the project are to are (1) to use immunoblot analysis to validate the biomarker as an indicator of camptothecin sensitivity using an available rabbit polyclonal antibody to screen a panel of cancer-derived and normal cell lines, (2) to evaluate 2 additional possible assay formats, and (3) to produce and evaluate a monoclonal antibody to this biomarker. The study will employ standard biological techniques, including cell-based viability assays, Western immunoblot assays, ELISA assays, immunohistochemistry, and enzymatic assays. The results of this study will be used to support a larger Phase 2 evaluation of human tumor specimens and to advance further commercial development.