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Gene expression of peripheral blood cells reveals pathways downstream of glucocorticoid receptor antagonism and nab-paclitaxel treatment

Maranville, Joseph C.a,b,c; Nanda, Ritab; Fleming, Gini F.b; Skor, Maxwell N.b; Di Rienzo, Annaa,c; Conzen, Suzanne D.a,b

doi: 10.1097/FPC.0000000000000077
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Objectives Whereas paclitaxel treatment is associated with leukopenia, the mechanisms that underlie this effect are not well-characterized. In addition, despite the importance of glucocorticoid signaling in cancer treatment, the genomic effects of glucocorticoid receptor antagonism by mifepristone treatment in primary human cells have never been described.

Methods As part of a randomized phase 1 clinical trial, we used microarrays to profile gene expression in peripheral blood cells sampled from each of four patients at baseline, after placebo/nanoparticle albumin-bound paclitaxel (nab-paclitaxel) treatment (cycle 1), and after mifepristone/nab-paclitaxel treatment (cycle 2).

Results We found that 63 genes were differentially expressed following treatment with nab-paclitaxel, including multiple genes in the tubulin pathway. We also found 606 genes that were differentially expressed in response to mifepristone; genes downregulated by mifepristone overlapped significantly with those previously identified as being upregulated by dexamethasone.

Conclusion These results provide insights into the mechanisms of paclitaxel and glucocorticoid receptor inhibition in peripheral blood cells.

Supplemental Digital Content is available in the text.

aCommittee on Clinical Pharmacology and Pharmacogenetics

Departments of bMedicine

cHuman Genetics, The University of Chicago, Chicago, Illinois, USA

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (www.pharmacogeneticsandgenomics.com).

Correspondence to Anna Di Rienzo, PhD, Department of Human Genetics, University of Chicago, 920 E. 58th Street, Rm. 424, Chicago, IL 60637, USA Tel: +1 773 834 1037; fax: +1 773 834 0505; e-mail: dirienzo@uchicago.edu or Suzanne D. Conzen, MD, Department of Medicine, University of Chicago, 5841 S. Maryland Ave., SBRI J301 MC 2115, Chicago, IL, 60637, USA Tel: +1 773 702 6149; fax: +1 773 702 0963; e-mail: sconzen@medicine.bsd.uchicago.edu

Received December 21, 2013

Accepted June 8, 2014

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins