We propose to use novel Palladium Catalyzed Chemical Amplification (PdCCA) technology to develop ultra-sensitive bioassays that can detect very low concentrations of tumor biomarkers in blood. PdCCA is a generic technology that can be universally applied to different assay platforms. In the bioassay application considered here it uses a detection antibody labeled with a palladium catalyst and a subsequent, palladium catalyzed, high gain redox reaction generating a water-soluble formazan dye. PdCCA will be adapted to the standard ELISA format, where it may provide a factor of 102 to 103 fold increase in sensitivity in immunoassays for which a detection antibody of high selectivity is available. This increase in sensitivity will lower the detection threshold of currently used methods to the desired range of ng-pg/ml, allowing for development of screening biomarkers for early tumor detection. Phase I of the proposed work will concentrate on technology development and optimization using a set of three biomarkers for ovarian cancer and, optionally, one biomarker of breast cancer, currently under study at the Fred Hutchinson Cancer Research Center, Seattle, WA (FHCRC). We will optimize the dye forming amplification chemistry and spectrophotometric detection, and use model in vitro assays to develop and optimize the bioassay technology. Feasibility of our approach will be demonstrated on clinical specimens stored at the FHCRC.
Public Health Relevance: Detection of cancer in the early, asymptomatic stages dramatically improves patients'survival, but currently there are no simple and reliable molecular diagnostic cancer screening tests. Even at early stages, tumors secrete specific molecular biomarkers, but their concentration in body fluids is typically significantly below the sensitivity of currently available assays. More sensitive detection platforms will facilitate the development of simple, non-invasive screening tests for early cancer diagnosis and treatment, leading to improved patient survival. Once PdCCA utility is demonstrated for the initial set of biomarkers, new tests for a variety of candidate molecular tumor markers will be developed, clinically verified and commercialized. The commercial product will consist of biomarker specific reagent kits and optimized detection procedures. Since we are taking advantage of the well established ELISA platform, this technology does not require any new equipment and is commercially attractive for a broad range of clinical applications. Availability of such tests will have a significant impact on early detection of disease and patient survival rates, as well as containment of the health care costs.
Thesaurus Terms: Atgn;Antibodies;Antigens;Assay;Blpi;Bioassay;Biologic Assays;Biologic Models;Biological Assay;Biological Models;Blood;Blood Reticuloendothelial System;Blood Serum;Body Fluids;Breast Cancer;Buffers;Ca-125;Ca-125 Antigen;Ca125;Cak1;Col1a1;Col1a1 Gene;Calibration;Cancer Antigen 125;Cancer Detection;Cancer Diagnostics;Cancer Patient;Cancer Screening For Patients;Cancer Staging;Cancer Treatment;Carbohydrate Antigen 125;Cell Communication And Signaling;Cell Signaling;Chemicals;Chemistry;Clinical;Clinical Treatment Moab;Coloring Agents;Complex;Containment;Detection;Development;Diagnostic;Diagnostic Neoplasm Staging;Disease;Disorder;Dyes;Elisa;Early Diagnosis;Enzyme-Linked Immunosorbent Assay;Equipment;Extinction;Extinction (Psychology);Formazans;Fred Hutchinson Cancer Research Center;Generic Drugs;Husi;Husi-I;Health Care Costs;Health Costs;Healthcare Costs;Human;Hydrogen Oxide;Immunoassay;Intracellular Communication And Signaling;Label;Literature;Msln;Msln Gene;Maintenance;Malignant Neoplasm Therapy;Malignant Neoplasm Treatment;Malignant Ovarian Neoplasm;Malignant Ovarian Tumor;Malignant Tumor Of The Ovary;Malignant Neoplasm Of Ovary;Man (Taxonomy);Medical;Mesothelin Gene;Metals;Method Loinc Axis 6;Methodology;Methods;Model System;Modeling;Modern Man;Molecular;Monitor;Monoclonal Antibodies;Neoplasm Staging;Nonproprietary Drugs;Optics;Ovary Cancer;Oxidation-Reduction;Palladium;Patients;Pd Element;Performance;Phase;Procedures;Reaction;Reagent;Redox;Research Specimen;Slpi;Slpi Gene;Slpia;Sampling;Screening For Cancer;Screening Procedure;Serum;Signal Transduction;Signal Transduction Systems;Signaling;Specimen;Staging;Survival Rate;T-Stage;Tm-Mkr;Technology;Temperature;Testing;Tetrazolium Salts;Time;Treatment Efficacy;Tumor Antigens;Tumor Markers;Tumor Staging;Tumor Stage;Tumor-Associated Antigen;Water;Work;Anticancer Therapy;Aqueous;Assay Development;Behavioral Extinction;Biological Signal Transduction;Biomarker;Cancer Diagnosis;Cancer Progression;Cancer Therapy;Catalyst;Clinical Applicability;Clinical Application;Density;Design;Designing;Developmental;Disease/Disorder;Early Cancer Detection;Early Detection;Generic;Immunogen;Improved;In Vitro Assay;Intervention Efficacy;Malignant Breast Neoplasm;Malignant Breast Tumor;Neoplasm Progression;Neoplastic Progression;Novel;Optical;Ovarian Cancer;Oxidation Reduction Reaction;Screening;Screenings;Technology Development;Tetrazolium;Therapeutic Efficacy;Therapeutically Effective;Therapy Efficacy;Tumor;Tumor Progression;Tumor-Specific Antigen
