title: Drug-eluting microarrays to identify effective chemotherapeutic combinations targeting patient-derived cancer stem cells.
abstract: A new paradigm in oncology establishes a spectrum of tumorigenic potential across the heterogeneous phenotypes within a tumor. The cancer stem cell hypothesis postulates that a minute fraction of cells within a tumor, termed cancer stem cells (CSCs), have a tumor-initiating capacity that propels tumor growth. An application of this discovery is to target this critical cell population using chemotherapy; however, the process of isolating these cells is arduous, and the rarity of CSCs makes it difficult to test potential drug candidates in a robust fashion, particularly for individual patients. To address the challenge of screening drug libraries on patient-derived populations of rare cells, such as CSCs, we have developed a drug-eluting microarray, a miniaturized platform onto which a minimal quantity of cells can adhere and be exposed to unique treatment conditions. Hundreds of drug-loaded polymer islands acting as drug depots colocalized with adherent cells are surrounded by a nonfouling background, creating isolated culture environments on a solid substrate. Significant results can be obtained by testing <6% of the cells required for a typical 96-well plate. Reliability was demonstrated by an average coefficient of variation of 14% between all of the microarrays and 13% between identical conditions within a single microarray. Using the drug-eluting array, colorectal CSCs isolated from two patients exhibited unique responses to drug combinations when cultured on the drug-eluting microarray, highlighting the potential as a prognostic tool to identify personalized chemotherapeutic regimens targeting CSCs.
authors.affiliation: J. Crayton Pruitt Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611;
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Carstens
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, OH 44195;
authors.forename: Robert C
authors.initials: RC
authors.lastname: Fisher
authors.affiliation: Department of Bioengineering, University of California, Berkeley, CA 94720;
authors.forename: Abhinav P
authors.initials: AP
authors.lastname: Acharya
authors.affiliation: Department of Surgery, University of Florida, Gainesville, FL 32610;
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Butterworth
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610;
authors.forename: Edward
authors.initials: E
authors.lastname: Scott
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, OH 44195; Department of Colorectal Surgery, Cleveland Clinic, Cleveland, OH 44195 huange2@ccf.org bkeselowsky@bme.ufl.edu.
authors.forename: Emina H
authors.initials: EH
authors.lastname: Huang
authors.affiliation: J. Crayton Pruitt Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611; huange2@ccf.org bkeselowsky@bme.ufl.edu.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Keselowsky
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016503:Drug Delivery Systems; D006801:Humans; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D014407:Tumor Cells, Cultured
keywords: cancer stem cell; chemopredictive; combination therapy; microarray; personalized medicine