TY  - JOUR
AU  - Reinartz, Roman
AU  - Wang, Shanshan
AU  - Kebir, Sied
AU  - Silver, Daniel J
AU  - Wieland, Anja
AU  - Zheng, Tong
AU  - Küpper, Marius
AU  - Rauschenbach, Laurèl
AU  - Fimmers, Rolf
AU  - Shepherd, Timothy M
AU  - Trageser, Daniel
AU  - Till, Andreas
AU  - Schäfer, Niklas
AU  - Glas, Martin
AU  - Hillmer, Axel M
AU  - Cichon, Sven
AU  - Smith, Amy A
AU  - Pietsch, Torsten
AU  - Liu, Ying
AU  - Reynolds, Brent A
AU  - Yachnis, Anthony
AU  - Pincus, David W
AU  - Simon, Matthias
AU  - Brüstle, Oliver
AU  - Steindler, Dennis A
AU  - Scheffler, Björn
TI  - Functional Subclone Profiling for Prediction of Treatment-Induced Intratumor Population Shifts and Discovery of Rational Drug Combinations in Human Glioblastoma.
JO  - Clinical cancer research
VL  - 23
IS  - 2
SN  - 1078-0432
CY  - Philadelphia, Pa. [u.a.]
PB  - AACR
M1  - DZNE-2020-05358
SP  - 562-574
PY  - 2017
AB  - 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.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.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.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.
KW  - Animals
KW  - Clonal Evolution: genetics
KW  - Drug Combinations
KW  - Drug Resistance, Neoplasm: genetics
KW  - Genetic Heterogeneity
KW  - Glioblastoma: drug therapy
KW  - Glioblastoma: genetics
KW  - Glioblastoma: pathology
KW  - Humans
KW  - Mice
KW  - Xenograft Model Antitumor Assays
KW  - Drug Combinations (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:27521447
C2  - pmc:PMC5241221
DO  - DOI:10.1158/1078-0432.CCR-15-2089
UR  - https://pub.dzne.de/record/139036
ER  -