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Clin Cancer Res. 2017 Jan 15;23(2):562-574. doi: 10.1158/1078-0432.CCR-15-2089. Epub 2016 Aug 12.

Functional Subclone Profiling for Prediction of Treatment-Induced Intratumor Population Shifts and Discovery of Rational Drug Combinations in Human Glioblastoma.

Author information

1
Stem Cell Pathologies, University of Bonn Medical Center, Bonn, Germany.
2
Institute of Reconstructive Neurobiology, University of Bonn Medical Center, Bonn, Germany.
3
Department of Neurosurgery, University of Florida, Gainesville, Florida.
4
Department of Cellular & Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio.
5
Institute for Medical Biometry, Informatics & Epidemiology, University of Bonn, Bonn, Germany.
6
Department of Neuroradiology, NYU Langone Medical Center, New York, New York.
7
LIFE & BRAIN GmbH, Bonn, Germany.
8
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore.
9
Division of Medical Genetics, University of Basel, Basel, Switzerland.
10
Health Cancer Center at Orlando Health, University of Florida, Orlando, Florida.
11
Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
12
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.
13
Department of Pathology, Immunology, & Lab Medicine, University of Florida, Gainesville, Florida.
14
Department of Neurosurgery, University of Bonn Medical Center, Bonn, Germany.
15
DZNE - German Center for Neurodegenerative Disease, Bonn, Germany.
16
JM USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts.
17
Stem Cell Pathologies, University of Bonn Medical Center, Bonn, Germany. b.scheffler@dkfz.de.
18
DKFZ-Division of Translational Oncology/Neurooncology, German Cancer Consortium (DKTK), Heidelberg & University Hospital Essen, Essen, Germany.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

PMID:
27521447
PMCID:
PMC5241221
DOI:
10.1158/1078-0432.CCR-15-2089
[Indexed for MEDLINE]
Free PMC Article

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