title: Functional Subclone Profiling for Prediction of Treatment-Induced Intratumor Population Shifts and Discovery of Rational Drug Combinations in Human Glioblastoma.
abstract: OBJECTIVE
  Investigation of clonal heterogeneity may be key to understanding mechanisms of therapeutic failure in human cancer. However, little is known on the consequences of therapeutic intervention on the clonal composition of solid tumors.
  
  
  METHODS
  Here, we used 33 single cell-derived subclones generated from five clinical glioblastoma specimens for exploring intra- and interindividual spectra of drug resistance profiles in vitro In a personalized setting, we explored whether differences in pharmacologic sensitivity among subclones could be employed to predict drug-dependent changes to the clonal composition of tumors.
  
  
  RESULTS
  Subclones from individual tumors exhibited a remarkable heterogeneity of drug resistance to a library of potential antiglioblastoma compounds. A more comprehensive intratumoral analysis revealed that stable genetic and phenotypic characteristics of coexisting subclones could be correlated with distinct drug sensitivity profiles. The data obtained from differential drug response analysis could be employed to predict clonal population shifts within the naïve parental tumor in vitro and in orthotopic xenografts. Furthermore, the value of pharmacologic profiles could be shown for establishing rational strategies for individualized secondary lines of treatment.
  
  
  CONCLUSIONS
  Our data provide a previously unrecognized strategy for revealing functional consequences of intratumor heterogeneity by enabling predictive modeling of treatment-related subclone dynamics in human glioblastoma. Clin Cancer Res; 23(2); 562-74. ©2016 AACR.
authors: Stem Cell Pathologies, University of Bonn Medical Center, Bonn, Germany.|Institute of Reconstructive Neurobiology, University of Bonn Medical Center, Bonn, Germany.
authors: Roman
authors: R
authors: Reinartz
authors: Department of Neurosurgery, University of Florida, Gainesville, Florida.
authors: Shanshan
authors: S
authors: Wang
authors: Stem Cell Pathologies, University of Bonn Medical Center, Bonn, Germany.|Institute of Reconstructive Neurobiology, University of Bonn Medical Center, Bonn, Germany.
authors: Sied
authors: S
authors: Kebir
authors: Department of Cellular & Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio.
authors: Daniel J
authors: DJ
authors: Silver
authors: Stem Cell Pathologies, University of Bonn Medical Center, Bonn, Germany.|Institute of Reconstructive Neurobiology, University of Bonn Medical Center, Bonn, Germany.
authors: Anja
authors: A
authors: Wieland
authors: Department of Neurosurgery, University of Florida, Gainesville, Florida.
authors: Tong
authors: T
authors: Zheng
authors: Stem Cell Pathologies, University of Bonn Medical Center, Bonn, Germany.|Institute of Reconstructive Neurobiology, University of Bonn Medical Center, Bonn, Germany.
authors: Marius
authors: M
authors: Küpper
authors: Stem Cell Pathologies, University of Bonn Medical Center, Bonn, Germany.|Institute of Reconstructive Neurobiology, University of Bonn Medical Center, Bonn, Germany.
authors: Laurèl
authors: L
authors: Rauschenbach
authors: Institute for Medical Biometry, Informatics & Epidemiology, University of Bonn, Bonn, Germany.
authors: Rolf
authors: R
authors: Fimmers
authors: Department of Neuroradiology, NYU Langone Medical Center, New York, New York.
authors: Timothy M
authors: TM
authors: Shepherd
authors: Stem Cell Pathologies, University of Bonn Medical Center, Bonn, Germany.|Institute of Reconstructive Neurobiology, University of Bonn Medical Center, Bonn, Germany.|LIFE & BRAIN GmbH, Bonn, Germany.
authors: Daniel
authors: D
authors: Trageser
authors: Stem Cell Pathologies, University of Bonn Medical Center, Bonn, Germany.|Institute of Reconstructive Neurobiology, University of Bonn Medical Center, Bonn, Germany.
authors: Andreas
authors: A
authors: Till
authors: Stem Cell Pathologies, University of Bonn Medical Center, Bonn, Germany.|Institute of Reconstructive Neurobiology, University of Bonn Medical Center, Bonn, Germany.
authors: Niklas
authors: N
authors: Schäfer
authors: Stem Cell Pathologies, University of Bonn Medical Center, Bonn, Germany.|Institute of Reconstructive Neurobiology, University of Bonn Medical Center, Bonn, Germany.|LIFE & BRAIN GmbH, Bonn, Germany.
authors: Martin
authors: M
authors: Glas
authors: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore.
authors: Axel M
authors: AM
authors: Hillmer
authors: Division of Medical Genetics, University of Basel, Basel, Switzerland.
authors: Sven
authors: S
authors: Cichon
authors: Health Cancer Center at Orlando Health, University of Florida, Orlando, Florida.
authors: Amy A
authors: AA
authors: Smith
authors: Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
authors: Torsten
authors: T
authors: Pietsch
authors: Department of Neurosurgery and Center for Stem Cell & Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Texas.
authors: Ying
authors: Y
authors: Liu
authors: Department of Neurosurgery, University of Florida, Gainesville, Florida.
authors: Brent A
authors: BA
authors: Reynolds
authors: Department of Pathology, Immunology, & Lab Medicine, University of Florida, Gainesville, Florida.
authors: Anthony
authors: A
authors: Yachnis
authors: Department of Neurosurgery, University of Florida, Gainesville, Florida.
authors: David W
authors: DW
authors: Pincus
authors: Department of Neurosurgery, University of Bonn Medical Center, Bonn, Germany.
authors: Matthias
authors: M
authors: Simon
authors: Institute of Reconstructive Neurobiology, University of Bonn Medical Center, Bonn, Germany.|LIFE & BRAIN GmbH, Bonn, Germany.|DZNE - German Center for Neurodegenerative Disease, Bonn, Germany.
authors: Oliver
authors: O
authors: Brüstle
authors: JM USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts.
authors: Dennis A
authors: DA
authors: Steindler
authors: Stem Cell Pathologies, University of Bonn Medical Center, Bonn, Germany. b.scheffler@dkfz.de.|Institute of Reconstructive Neurobiology, University of Bonn Medical Center, Bonn, Germany.|LIFE & BRAIN GmbH, Bonn, Germany.|DKFZ-Division of Translational Oncology/Neurooncology, German Cancer Consortium (DKTK), Heidelberg & University Hospital Essen, Essen, Germany.
authors: Björn
authors: B
authors: Scheffler
mesh_terms: D000818:Animals; D060965:Clonal Evolution / Q000235:genetics; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D018740:Genetic Heterogeneity; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D051379:Mice; D023041:Xenograft Model Antitumor Assays
chemical_list: D004338:Drug Combinations