Abstract:
: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.
journal_name
Front Pharmacoljournal_title
Frontiers in pharmacologyauthors
Barrett MT,Lenkiewicz E,Evers L,Holley T,Ruiz C,Bubendorf L,Sekulic A,Ramanathan RK,Von Hoff DDdoi
10.3389/fphar.2013.00002subject
Has Abstractpub_date
2013-01-28 00:00:00pages
2issn
1663-9812journal_volume
4pub_type
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pub_type: 杂志文章,收录出版
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