Clonal Evolution and Therapeutic Resistance in Solid Tumors

Tumors frequently arise as a result of an acquired genomic instability and the subsequent evolution of neoplastic populations with variable genomes. A barrier to the study of the somatic genetics of human solid tumors in vivo is the presence of admixtures of non-neoplastic cells with normal genomes...

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Main Authors:	Barrett, Michael T., Lenkiewicz, Elizabeth, Evers, Lisa, Holley, Tara, Ruiz, Christian, Bubendorf, Lukas, Sekulic, Aleksander, Ramanathan, Ramesh K., Von Hoff, Daniel D.
Format:	Online
Language:	English
Published:	Frontiers Media S.A. 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3556559/

id	pubmed-3556559
recordtype	oai_dc
spelling	pubmed-35565592013-01-31 Clonal Evolution and Therapeutic Resistance in Solid Tumors Barrett, Michael T. Lenkiewicz, Elizabeth Evers, Lisa Holley, Tara Ruiz, Christian Bubendorf, Lukas Sekulic, Aleksander Ramanathan, Ramesh K. Von Hoff, Daniel D. Pharmacology Tumors frequently arise as a result of an acquired genomic instability and the subsequent evolution of neoplastic populations with variable genomes. A barrier to the study of the somatic genetics of human solid tumors in vivo is the presence of admixtures of non-neoplastic cells with normal genomes in patient samples. These can obscure the presence of somatic aberrations including mutations, homozygous deletions, and breakpoints in biopsies of interest. Furthermore, clinical samples frequently contain multiple neoplastic populations that cannot be distinguished by morphology. Consequently, it is difficult to determine whether mutations detected in a sample of interest are concurrent in a single clonal population or if they occur in distinct cell populations in the same sample. The advent of targeted therapies increases the selection for preexisting populations. However the asymmetric distribution of therapeutic targets in clonal populations provides a mechanism for the rapid evolution of resistant disease. Thus, there is a need to not only isolate tumor from normal cells, but to also enrich distinct populations of clonal neoplastic cells in order to apply genome technologies to identify clinically relevant genomic aberrations that drive disease in patients in vivo. To address this we have applied single and multiparameter DNA content based flow assays to the study of solid tumors. Our work has identified examples of clonal resistance to effective therapies. This includes androgen withdrawal in advanced prostate cancer. In addition we demonstrate examples of co-existing clonal populations with highly aberrant genomes and ploidies in a wide variety of solid tumors. We propose that clonal analysis of tumors, based on flow cytometry and high resolution genome analyses of purified neoplastic populations, provides a unique approach to the study of therapeutic responses and the evolution of resistance. Frontiers Media S.A. 2013-01-28 /pmc/articles/PMC3556559/ /pubmed/23372550 http://dx.doi.org/10.3389/fphar.2013.00002 Text en Copyright © 2013 Barrett, Lenkiewicz, Evers, Holley, Ruiz, Bubendorf, Sekulic, Ramanathan and Von Hoff. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Barrett, Michael T. Lenkiewicz, Elizabeth Evers, Lisa Holley, Tara Ruiz, Christian Bubendorf, Lukas Sekulic, Aleksander Ramanathan, Ramesh K. Von Hoff, Daniel D.
spellingShingle	Barrett, Michael T. Lenkiewicz, Elizabeth Evers, Lisa Holley, Tara Ruiz, Christian Bubendorf, Lukas Sekulic, Aleksander Ramanathan, Ramesh K. Von Hoff, Daniel D. Clonal Evolution and Therapeutic Resistance in Solid Tumors
author_facet	Barrett, Michael T. Lenkiewicz, Elizabeth Evers, Lisa Holley, Tara Ruiz, Christian Bubendorf, Lukas Sekulic, Aleksander Ramanathan, Ramesh K. Von Hoff, Daniel D.
author_sort	Barrett, Michael T.
title	Clonal Evolution and Therapeutic Resistance in Solid Tumors
title_short	Clonal Evolution and Therapeutic Resistance in Solid Tumors
title_full	Clonal Evolution and Therapeutic Resistance in Solid Tumors
title_fullStr	Clonal Evolution and Therapeutic Resistance in Solid Tumors
title_full_unstemmed	Clonal Evolution and Therapeutic Resistance in Solid Tumors
title_sort	clonal evolution and therapeutic resistance in solid tumors
description	Tumors frequently arise as a result of an acquired genomic instability and the subsequent evolution of neoplastic populations with variable genomes. A barrier to the study of the somatic genetics of human solid tumors in vivo is the presence of admixtures of non-neoplastic cells with normal genomes in patient samples. These can obscure the presence of somatic aberrations including mutations, homozygous deletions, and breakpoints in biopsies of interest. Furthermore, clinical samples frequently contain multiple neoplastic populations that cannot be distinguished by morphology. Consequently, it is difficult to determine whether mutations detected in a sample of interest are concurrent in a single clonal population or if they occur in distinct cell populations in the same sample. The advent of targeted therapies increases the selection for preexisting populations. However the asymmetric distribution of therapeutic targets in clonal populations provides a mechanism for the rapid evolution of resistant disease. Thus, there is a need to not only isolate tumor from normal cells, but to also enrich distinct populations of clonal neoplastic cells in order to apply genome technologies to identify clinically relevant genomic aberrations that drive disease in patients in vivo. To address this we have applied single and multiparameter DNA content based flow assays to the study of solid tumors. Our work has identified examples of clonal resistance to effective therapies. This includes androgen withdrawal in advanced prostate cancer. In addition we demonstrate examples of co-existing clonal populations with highly aberrant genomes and ploidies in a wide variety of solid tumors. We propose that clonal analysis of tumors, based on flow cytometry and high resolution genome analyses of purified neoplastic populations, provides a unique approach to the study of therapeutic responses and the evolution of resistance.
publisher	Frontiers Media S.A.
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3556559/
_version_	1611950059308449792

Clonal Evolution and Therapeutic Resistance in Solid Tumors

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