文章基本信息

标题：Drug-eluting microarrays to identify effective chemotherapeutic combinations targeting patient-derived cancer stem cells
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作者：Matthew R. Carstens ; Robert C. Fisher ; Abhinav P. Acharya 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：28
页码：8732-8737
DOI：10.1073/pnas.1505374112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceCancer research has relied on in vitro experiments with established cell lines to investigate the efficacy of chemotherapy drug panels, which limit clinical correlation. Targeting tumor-initiating cells could be a viable clinical strategy, but these cells are extremely rare, necessitating new methods for rapid and robust screening. We developed a miniaturized platform to investigate the chemosensitivity of patient-derived tumor-initiating cells using limited cell numbers. The miniature platform described herein represents, to our knowledge, the first demonstration of a cell patterning technique that combines the ability to release small molecule drugs, alone or in combination, to separate islands of cells. This device can be adopted in clinical and academic laboratories targeting cancer stem cell populations to tailor patient-specific chemotherapeutic treatment options. 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.
关键词：personalized medicine ; chemopredictive ; cancer stem cell ; microarray ; combination therapy