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

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

SUBMITTER: Maranville JC

PROVIDER: S-EPMC4122588 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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

Maranville Joseph C JC Nanda Rita R Fleming Gini F GF Skor Maxwell N MN Di Rienzo Anna A Conzen Suzanne D SD

Pharmacogenetics and genomics 20140901 9

<h4>Objectives</h4>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.<h4>Methods</h4>As part of a randomized phase 1 clinical trial, we used microarrays to profile gene expression in peripheral blood cel ...[more]

PMID: 25000515

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Project description:Triple-negative breast cancer (TNBC) accounts for 10% to 20% of newly diagnosed invasive breast cancer. Finding effective targets for chemotherapy-resistant TNBC has proven difficult in part because of TNBC's molecular heterogeneity. We have previously reported that likely because of the antiapoptotic activity of glucocorticoid receptor (GR) in estrogen receptor (ER)-negative breast epithelial and cancer cells, high GR expression/activity in early-stage TNBC significantly correlates with chemotherapy resistance and increased recurrence. We hypothesized that pretreatment with mifepristone, a GR antagonist, would potentiate the efficacy of chemotherapy in GR+ TNBCs by inhibiting the antiapoptotic signaling pathways of GR and increasing the cytotoxic efficiency of chemotherapy.TNBC cell apoptosis was examined in the context of physiologic glucocorticoid concentrations, chemotherapy, and/or pharmacologic concentrations of mifepristone. We used high-throughput live microscopy with continuous recording to measure apoptotic cells stained with a fluorescent dye and Western blot analysis to detect caspase-3 and PARP cleavage. The effect of mifepristone on GR-mediated gene expression was also measured. TNBC xenograft studies were performed in female severe combined immunodeficient (SCID) mice and tumors were measured following treatment with vehicle, paclitaxel, or mifepristone/paclitaxel.We found that although mifepristone treatment alone had no significant effect on TNBC cell viability or clonogenicity in the absence of chemotherapy, the addition of mifepristone to dexamethasone/paclitaxel treatment significantly increased cytotoxicity and caspase-3/PARP cleavage. Mifepristone also antagonized GR-induced SGK1 and MKP1/DUSP1 gene expression while significantly augmenting paclitaxel-induced GR+ MDA-MB-231 xenograft tumor shrinkage in vivo.These results suggest that mifepristone pretreatment could be a useful strategy for increasing tumor cell apoptosis in chemotherapy-resistant GR+ TNBC.

Project description:BACKGROUND:Nanoparticle albumin-bound paclitaxel (nab-P) plus gemcitabine (Gem) became a standard treatment option for metastatic pancreatic cancer (MPC) following positive results from a global phase III trial (MPACT). A large number of studies have now published results on the use of nab-P/Gem to treat advanced and early-stage disease, warranting a comprehensive review. The main goal of this systematic review is to summarize the efficacy and safety data of nab-P/Gem for the treatment of pancreatic cancer (PC). METHODS:This systematic review includes results from studies that either published results in a peer-reviewed journal or presented the results at a major oncology conference. RESULTS:Sixty-two studies were included (50 in the advanced/metastatic setting and 12 in the locally advanced setting). Most studies on the treatment of MPC were exclusively first line (33/50). Nevertheless, the studies in this review comprised a broad spectrum of patients, including those <65 and ?65 years of age and those with a Karnofsky performance status of 70-100. Median overall survival (OS) in studies of nab-P/Gem in the advanced/metastatic setting ranged from 8.7 to 13.5 months. In addition, 15 studies of patients with advanced/metastatic PC examined nab-P/Gem as a backbone on which to add a variety of agents, including cancer stem cell inhibitors, stromal disrupting agents, and immune-modulating agents (median OS, 6.9-17 months). Ongoing trials are investigating nab-P/Gem with or without other agents across disease settings. DISCUSSION:Studies conducted after MPACT have demonstrated that nab-P/Gem is an effective regimen for the first-line treatment of MPC for a wide range of patients. Regimens using nab-P/Gem as a backbone on which to combine additional agents are being studied actively, particularly in the advanced disease setting. Ongoing studies will yield valuable insights on the utility of nab-P-containing regimens to improve patient outcomes in PC in both earlier-stage and advanced disease.

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

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

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