title: Using heterogeneity of the patient-derived xenograft model to identify the chemoresistant population in ovarian cancer.
abstract: A cornerstone of preclinical cancer research has been the use of clonal cell lines. However, this resource has underperformed in its ability to effectively identify novel therapeutics and evaluate the heterogeneity in a patient's tumor. The patient-derived xenograft (PDX) model retains the heterogeneity of patient tumors, allowing a means to not only examine efficacy of a therapy, but also basic tenets of cancer biology in response to treatment. Herein we describe the development and characterization of an ovarian-PDX model in order to study the development of chemoresistance. We demonstrate that PDX tumors are not simply composed of tumor-initiating cells, but recapitulate the original tumor's heterogeneity, oncogene expression profiles, and clinical response to chemotherapy. Combined carboplatin/paclitaxel treatment of PDX tumors enriches the cancer stem cell populations, but persistent tumors are not entirely composed of these populations. RNA-Seq analysis of six pair of treated PDX tumors compared to untreated tumors demonstrates a consistently contrasting genetic profile after therapy, suggesting similar, but few, pathways are mediating chemoresistance. Pathways and genes identified by this methodology represent novel approaches to targeting the chemoresistant population in ovarian cancer.
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alabama at Birmingham. NIH Medical Scientist Training Program, University of Alabama at Birmingham.
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Dobbin
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alabama at Birmingham.
authors.forename: Ashwini A
authors.initials: AA
authors.lastname: Katre
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alabama at Birmingham.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Steg
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alabama at Birmingham.
authors.forename: Britt K
authors.initials: BK
authors.lastname: Erickson
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alabama at Birmingham.
authors.forename: Monjri M
authors.initials: MM
authors.lastname: Shah
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alabama at Birmingham.
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Alvarez
authors.affiliation: Department of Pathology, University of Alabama at Birmingham.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Conner
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham.
authors.forename: David
authors.initials: D
authors.lastname: Schneider
authors.affiliation: Division of Preventative Medicine, Department of Medicine, University of Alabama at Birmingham.
authors.forename: Dongquan
authors.initials: D
authors.lastname: Chen
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The University of Virginia, Charlottesville, VA.
authors.forename: Charles N
authors.initials: CN
authors.lastname: Landen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D016513:Mice, SCID; D008875:Middle Aged; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018579:Patient Selection; D016133:Polymerase Chain Reaction; D057285:Precision Medicine; D011237:Predictive Value of Tests; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor