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Transcription profiling of human myeloma cells following short term in-vivo drug exposure

ABSTRACT: In vivo changes of gene expression profiles (GEP) of tumor cells 48hr after single agent therapy may vary by treatment and provide added predictive power over baseline GEP information. In newly diagnosed patients with multiple myeloma (MM), GEP data were obtained on tumor cells prior to and 48hr after dexamethasone (n=45) or thalidomide treatment (n=42); in case of relapsed MM, GEP data were obtained prior to (n=36) and after (n=19) lenalidomide administration. Dexamethasone and thalidomide induced both common and unique GEP changes. Combined baseline and 48hr changes of GEP in a subset of genes that were discovered in newly diagnosed MM also predicted event-free and overall survival in relapsed patients receiving lenalidomide. Combined with baseline molecular features, changes in GEP following short-term single agent treatment may help guide treatment decisions for patients with MM. The genes whose altered expression is related to eventual survival may also point to mechanisms of action and resistance to different classes of drugs. Experiment Overall Design: See above (Series_summary)

ORGANISM(S): Homo sapiens

SUBMITTER: Fenghuang Zhan

PROVIDER: E-GEOD-8546 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Gene Expression Changes in Myeloma Cells Following Short Term In-vivo Drug Exposure

Project description:In vivo changes of gene expression profiles (GEP) of tumor cells 48hr after single agent therapy may vary by treatment and provide added predictive power over baseline GEP information. In newly diagnosed patients with multiple myeloma (MM), GEP data were obtained on tumor cells prior to and 48hr after dexamethasone (n=45) or thalidomide treatment (n=42); in case of relapsed MM, GEP data were obtained prior to (n=36) and after (n=19) lenalidomide administration. Dexamethasone and thalidomide induced both common and unique GEP changes. Combined baseline and 48hr changes of GEP in a subset of genes that were discovered in newly diagnosed MM also predicted event-free and overall survival in relapsed patients receiving lenalidomide. Combined with baseline molecular features, changes in GEP following short-term single agent treatment may help guide treatment decisions for patients with MM. The genes whose altered expression is related to eventual survival may also point to mechanisms of action and resistance to different classes of drugs. Keywords: drug response

2008-08-04 | GSE8546 | GEO

Thalidomide in Total Therapy 2 Overcomes Inferior Prognosis of Myeloma with Low Expression of the Glucocorticoid Receptor Gene NR3C1

Project description:Purpose: Because dexamethasone remains a key component of myeloma therapy, we wished to examine the correlation of baseline and relapse expression levels of the glucocorticoid receptor gene NR3C1 with other clinical features. Experimental Design: We investigated the clinical impact of gene expression profiling (GEP)–derived expression levels of NR3C1 in 351 patients with GEP data available at baseline and in 130 with data available at relapse, among 668 subjects accrued to Total Therapy 2 (TT2). The effect of the expression of NR3C1 at baseline (previously published under GSE2685) and at relapse was analyzed in the context of treatment (thalidomide vs. no thalidomide) and other clinical parameters.

2012-11-05 | E-GEOD-38627 | biostudies-arrayexpress

Maturation of the thalidomystery

Project description:Gene expression profile (GEP) was analyzed from cultured bone marrow (BM) samples of patients with lenalidomide-responsive versus lenalidomide-resistant myeloma after 24 hours incubation in vitro with thalidomide (Thal) (0.8 Âµg/ml), lenalidomide (Len) (0.5 Âµg/ml) or with DMSO (control). Comparative gene expression profile of cultured bone marrow samples from patients with lenalidomide responsive versus lenalidomide resistant myeloma after 24 hours incubation in vitro with thalidomide, lenalidomide or DMSO (control).

2014-08-26 | E-GEOD-60742 | biostudies-arrayexpress

Maturation of the thalidomystery

2014-08-26 | GSE60742 | GEO

Impact of Gene Expression Profiling Based Risk Stratification in Patients with Myeloma Receiving Initial Therapy with Lenalidomide and Dexamethasone

Project description:Detection of specific chromosomal abnormalities by FISH and metaphase cytogenetics allows risk stratification in multiple myeloma (MM); however, gene expression profiling (GEP) based signatures may enable more specific risk categorization. We examined the utility of two GEP-based risk stratification systems among patients undergoing initial therapy with lenalidomide in the context of a phase 3 trial. The E4A03 clinical trial randomized patients with previously untreated MM to lenalidomide and either standard-dose dexamethasone. Baseline bone marrow samples were obtained from consenting patients. The marrow aspirates were subjected to a fully automated ROBOSEP cell separation system that utilizes immunomagnetic technology to positively select for CD 138+ cells. The purity of the sorting was confirmed by 3-color immunofluorescent slide based assessment on the sorted cells. The plasma cell gene expression proﬁles were analyzed using U133 Plus 2.0 array. All samples were run individually with no pooling. The GEP-70 signature was determined as previously described, using log2 transformed raw MAS 5.0 signals. The GEP15 classification was performed as previously described, with the patients in highest quartile for the risk score being considered as high risk.

2011-08-25 | E-GEOD-31504 | biostudies-arrayexpress

Gene expression profiles of patients with multiple myeloma who have been treated previously

Project description:This Series represents the gene expression profiles of patients with multiple myeloma who have been treated previously. In brief, Total Therapy 6 (TT6) is an open label phase 2 protocol for patients with symptomatic multiple myeloma, who had been treated with more than one cycle of prior therapy excluding autologous hematopoietic stem cell transplant. This protocol was approved by the institutional review board on March 25, 2009 (IRB#108053). The TT6 treatment regimen consists of induction therapy with Melphalan/Bortezomib/Thalidomide/Dexamethasone/Cisplatin/Doxorubicin/Cyclophosphamide/Etoposide (M-VTD-PACE) followed by a high dose M-VTD-PACE based tandem transplant. Maintenance therapy consists of Bortezomib/Lenalidomide/Dexamethasone alternating with Borteomib/Melphalan/Dexamethasone every months for 3 years. We analyzed CD138+ selected cells of previously treated MM patients by microarray.

2015-01-20 | E-GEOD-57317 | biostudies-arrayexpress

Single cell RNA-seq of relapsed and refractory multiple myeloma patients defines new resistance pathways and targeted treatments

Project description:Multiple myeloma (MM) is a neoplastic plasma cell (PC) disorder, characterized by clonal proliferation of malignant PC. Despite extensive research, disease heterogeneity within and between treatment resistant patients is poorly characterized. Here, we conduct a prospective multi-center single-arm clinical trial (NCT04065789), combined with longitudinal single cell RNA-seq to study the molecular dynamics of MM resistance mechanisms. Forty-one newly diagnosed MM patients who either failed to respond or experienced early relapse after a bortezomib-containing induction regimen, were enrolled to evaluate the safety and efficacy of a daratumumab/carfilzomib/lenalidomide/dexamethasone combination. Primary clinical endpoint was safety and tolerability. Secondary endpoints included overall response rate; progression free survival, and overall survival. Treatment was safe and well-tolerated, deep and durable responses were achieved. In prespecified exploratory analyses, comparison of 41 primary-refractory and early-relapsed patients with 11 healthy subjects and 15 newly diagnosed MM patients revealed new MM molecular pathways of resistance, including hypoxia tolerance, protein folding, and mitochondria respiration, that generalized to larger clinical cohorts (CoMMpass). We found peptidylprolyl isomerase A (PPIA), a central gene in the protein-folding response pathway, as a potential new target for resistant MM. CRISPR/Cas9 deletion of PPIA or inhibition of PPIA with cyclosporin A significantly sensitizes MM tumor cells to proteasome inhibitors. Together, our study defines a roadmap for integrating scRNA-seq in clinical trials, identifies a signature of highly resistant MM patients and discovers PPIA as a potent therapeutic target for these tumors.

2021-01-27 | GSE161195 | GEO

The BET bromodomain inhibitor CPI203 improves lenalidomide activity in in vitro and in vivo models of multiple myeloma by synergistic blockade of Ikaros and c-Myc signaling

Project description:Multiple myeloma (MM) cells were treated with the BET inhibitor CPI203 alone and in combination with lenalidomide plus dexamethasone in vitro and in vivo (mouse xenograft). We used microarrays to uncover the mechanisms underlying CPI-203 activity in MM, alone and in combination with lenalidomide plus dexamethasone (combo).

2016-09-28 | GSE87403 | GEO

Cereblon expression is required for the anti-myeloma activity of lenalidomide and pomalidomide [expression profiling]

Project description:The precise molecular mechanism of action and targets through which thalidomide and related immunomodulatory drugs (IMiDs) exert their anti-tumor effects remains unclear. We investigated the role of cereblon (CRBN), a primary teratogenic target of thalidomide, in the anti-myeloma activity of IMiDs. CRBN depletion is initially cytotoxic to human myeloma cells but surviving cells with stable CRBN depletion become highly resistant to both lenalidomide and pomalidomide, but not to the unrelated drugs bortezomib, dexamethasone and melphalan. Acquired deletion of CRBN was found to be the primary genetic event differentiating isogenic MM1.S cell lines cultured to be sensitive or resistant to lenalidomide and pomalidomide. Gene expression changes induced by lenalidomide were dramatically suppressed in the presence of CRBN depletion further demonstrating that CRBN is required for lenalidomide activity. Downstream targets of CRBN include interferon regulatory factor 4 (IRF4) previously reported to also be a target of lenalidomide. Patients exposed to and putatively resistant to lenalidomide had lower CRBN levels in paired samples before and after therapy. In summary, CRBN is an essential requirement for IMiD activity, and a possible biomarker for the clinical assessment of anti-myeloma efficacy. We included 15 samples from multiple myeloma cell lines.

2011-09-30 | E-GEOD-31421 | biostudies-arrayexpress

Expression data from BM-CD138+, obtained from newly diagnosed Multiple Myeloma patients

Project description:A subanalysis of the GIMEMA-MMY-3006 trial was performed to characterize treatment-emergent peripheral neuropathy (PN) in patients randomized to thalidomide-dexamethasone (TD) or bortezomib-TD (VTD) before and after double autologous transplantation (ASCT) for multiple myeloma (MM). 236 patients randomized to VTD and 238 to TD were stratified according to the emergence of grade ≥2 PN. Gene expression profiles (GEP) of CD138+ plasma cells were analyzed from 122 VTD-treated patients. The incidence of grade ≥2 PN was 35% in the VTD arm and 10% in the TD arm (p<0.001). PN resolved in 88% and 95% of patients in VTD and TD groups, respectively. Rates of complete/near complete response, progression-free and overall survival were not adversely affected by emergence of grade ≥2 PN. Baseline characteristics were not risk factors for PN, while GEP analysis revealed the deregulated expression of genes implicated in cytoskeleton rearrangement, neurogenesis and axonal guidance. In conclusion, in comparison with TD, incorporation of VTD into ASCT was associated with a higher incidence of PN which, however, was reversible in most of the patients and did not adversely affect their outcomes nor their ability to subsequently receive ASCT. GEP analysis suggests an interaction between myeloma genetic profiles and development of VTD-induced PN.

2014-12-23 | GSE58133 | GEO

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