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Ex Vivo Drug Sensitivity Testing As a Means for Drug Repurposing in Esophageal Adenocarcinoma

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Ex Vivo Drug Sensitivity Testing As a Means for Drug Repurposing in Esophageal Adenocarcinoma RESEARCH ARTICLE Ex vivo drug sensitivity testing as a means for drug repurposing in esophageal adenocarcinoma Ines Lohse1,2,3, Hassan Al-Ali4,5,6,7, Claude-Henry Volmar1,2,3, Annamil D. Alvarez Trotta4,8,9, Shaun P. Brothers1,2,3, Anthony J. Capobianco4,8,9, Claes Wahlestedt1,2* 1 Center for Therapeutic Innovation, Miller School of Medicine, University of Miami, Miami, Florida, United States of America, 2 Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, Florida, United States of America, 3 Molecular Therapeutics Shared Resource, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, United States of America, a1111111111 4 Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, United States of America, a1111111111 5 Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, Florida, United a1111111111 States of America, 6 Department of Neurological Surgery, Miller School of Medicine, University of Miami, a1111111111 Miami, Florida, United States of America, 7 Peggy and Harold Katz Drug Discovery Center, Department of a1111111111 Medicine, Miller School of Medicine, University of Miami, Miami, Florida, United States of America, 8 Molecular Oncology Program, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida, United States of America, 9 Division of Surgical Oncology, DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida, United States of America OPEN ACCESS * [email protected] Citation: Lohse I, Al-Ali H, Volmar C-H, D. Alvarez Trotta A, Brothers SP, Capobianco AJ, et al. (2018) Ex vivo drug sensitivity testing as a means for drug Abstract repurposing in esophageal adenocarcinoma. PLoS ONE 13(9): e0203173. https://doi.org/10.1371/ journal.pone.0203173 Background Editor: Javier S. Castresana, University of Navarra, SPAIN Esophageal cancer remains one of the hardest cancers to treat with rising incidence rates, Received: June 13, 2018 low overall survival and high levels of treatment resistance. The lack of clinically available biomarkers hinder diagnosis and treatment stratification. While large scale sequencing Accepted: August 15, 2018 approaches have uncovered a number of molecular makers, little has translated in the rou- Published: September 13, 2018 tine treatment of esophageal cancer patients. Copyright: © 2018 Lohse et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which Material and methods permits unrestricted use, distribution, and reproduction in any medium, provided the original We evaluate the treatment response towards a panel of 215 FDA-approved and 163 epige- author and source are credited. netic compounds of 4 established and 2 patient-derived esophageal cancer cell lines. Cell Data Availability Statement: All relevant data are viability was evaluated after 72h of treatment using cell titer glow. The drug sensitivity testing within the paper and its Supporting Information results for gemcitabine and cisplatin were validated using clonogenic assays. files. Funding: SB received support from the National Institutes of Health (R01NS092671 and Results R01MH110441). CW's laboratory is currently The tested cell lines display different drug sensitivity profiles, although we found compounds publically funded by NIH grants DA035592, that display efficacy in all of the tested established or patient-derived cell lines. Clonogenic DA035055 and AA023781, and Florida Department of Health grants 6AZ08 and 7AZ26. The funders assays confirmed the validity of the drug sensitivity testing results. Using the epigenetic had no role in study design, data collection and library, we observed high sensitivity towards a number of epigenetic modifiers. PLOS ONE | https://doi.org/10.1371/journal.pone.0203173 September 13, 2018 1 / 12 Esophageal cancer screening analysis, decision to publish, or preparation of the Discussion manuscript. Ex vivo drug sensitivity testing may present a viable option for the treatment stratification of Competing interests: The authors have declared esophageal cancer patients and holds the potential to greatly improve patient outcome that no competing interests exist. while reducing treatment toxicity. Introduction Esophageal cancer is the 8th most common cause of cancer death in Western countries with rising incidence rates of adenocarcinoma of the lower esophagus and esophagogastric junction [1]. Although the prognosis for early stage disease is favorable, overall survival remains low at 19% despite advances in surgical techniques and multimodal therapies [1, 2]. Apart from the ERBB2/HER2 status, no biomarkers that complement or improve the diagnosis, risk stratifica- tion and therapy of the disease as part of routine clinical practice [3]. A number of recent high-throughput investigations revealed histological, genetic and epige- netic changes typical for esophageal adenocarcinoma [3]. While, these studies have uncovered a number of mutations and revealed an aberrant methylation of the genome [4±7], little has translated into clinical practice to date. However, a number of clinical trials currently evaluate whether the utility of genomic and epigenetic markers for early detection, prognosis and pre- diction of response to treatment [4±6, 8]. Optimal pre-clinical staging based on the American Joint Committee on Cancer (AJCC) Staging System based on tumor-node-metastasis (TNM) sub-classifications [2, 9, 10] remains crucial in optimizing outcomes for patients with esoph- ageal adenocarcinoma [2]. Precision medicine approaches for the treatment stratification of patients with esophageal adenocarcinoma have recently come into the focus of the field in order to improve patient out- come. Apart from improvements in PET imaging techniques [11, 12], the lack of available material from biopsies, long turn over times of sequencing approaches and failure to detect targetable mutations have prevented the clinical application [13]. We have overcome these issues by adapting a drug sensitivity testing (DST) platform previ- ously established for the stratification of patients with relapsed/refractory AML [14]. Ex vivo DST screening allows the identification of patient-specific treatments from a library of 215 FDA-approved compounds that are available on compassionate care and may present a new stratification approach for esophageal adenocarcinoma patients [14]. Material and methods Esophageal cell lines OE33, OE19 and SKGT2 human esophageal adenocarcinoma cell lines were obtained from the European Collection of Cell Culture (ATCC). Flo1, EAC42 and EAC47 cells were established in the Capobianco Laboratory. EAC42 and EAC47 human esophageal adenocarcinoma cell lines are derived from patients undergoing surgery at the Miller School of Medicine, Univer- sity of Miami [15]. The Capobianco laboratory obtained written informed consent from all patients and approval from the Institutional Research Ethics Committee. The normal esophageal epithelium cell line EACN42 was established in the Capobianco lab- oratory. The cell lines was derived from human normal epithelium and immortalized using HPV E6-E7. PLOS ONE | https://doi.org/10.1371/journal.pone.0203173 September 13, 2018 2 / 12 Esophageal cancer screening FDA library drug sensitivity testing Drug sensitivity testing (DST) was performed as described previously [14]. Briefly, a range of 215 FDA/EMA (Food and Drug Administration/European Medicines Agency)-approved anti- cancer drugs were represented in the compound library, covering a variety of targets and path- ways relevant to cancer in general and esophageal cancer specifically (Table 1). Individual drugs were dissolved in 100% DMSO and tested in duplicates starting at a maximal test con- centration of 10μM then over a 20,000-fold concentration range to generate dose response curves. Wells with assay buffer containing DMSO served as negative controls. 1000 exponen- tially growing cells were seeded per well in 384-well micro-titer plates and incubated in the presence of compounds in a humidified environment at 37ÊC and 5% CO2. After 72 hours of treatment, cell viability was assessed by measuring ATP levels via bioluminescence (CellTiter- Glo, Promega) according to manufactures recommendations. Interpretation of curve parame- ters was performed according to the modified drug sensitivity scoring (DSSmod) function developed by Swords et al [14]. As a final step, the selective DSSmod (sDSSmod) for each drug in each patient screen is calculated according to the formula sDSSmod = DSSmod (patient cells)Ð Table 1. Compound library for ex vivo drug sensitivity screening. All listed agents are FDA-approved and classified according to mechanism of action where available. Class Compound Alkylating agents Bendamustine, Busulfan, Carboplatin, Cisplatin, Cyclophosphamide, Dacarbazine, lfosfamide, lomustine, Methazolastone, Oxaliplatin, Procarbazine, Streptozotocin Antimetabolites Azacitidine, Azaguanine-8, Capecitabine, Carmofur, Cladrabine, Clofarabine, Cytarabine, Decitabine, Febuxostat, Floxuridine, Fludarabine, Fluorouracil, Ftorafur, Gemcitabine, lonidamine, Mercaptopurine, Methotrexate, Nelarabine, Pemetrexed, Thioguanine Antimitotics 10-Deacetylbaccatin, Cephalomannine, Docetaxel, Paclitaxel, Vinblastine, Vincristine Antitumor antibiotics Artemether, Azithromycin, Bacitracin, Bleomycin, Hygromycin B, Lincomycin, Methacycline, Ofloxacin
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