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Machine learning-assisted classification of responders and non-responders to bortezomib treatment regimens PAD and VCD using new experimental dataset of 58 multiple myeloma RNA sequencing profiles

ABSTRACT: Multiple myeloma (MM) is a hematological cancer which arises from abnormal antibody producing white blood plasma cells. MM affected approximately 500 000 people and results in ~100 000 deaths annually, being currently considered treatable but uncurable. There are several MM chemotherapy treatment regimens, among which ten include bortezomib, a proteasome-targeted drug. Patients with MM respond differently on bortezomib, and new prognostic biomarkers are needed to personalize treatments. However, there is a shortage of clinically annotated molecular profiles of MM that could be used to establish novel molecular diagnostics. In this study we report new molecular profiles for 58 MM patients annotated with data on two chemotherapy regimens which include bortezomib, doxorubicin, and dexamethasone (PAD) or bortezomib, cyclophosphamide, and dexamethasone (VCD). MM biosamples were taken prior to first line chemotherapy treatments and subjected to RNA sequencing.

ORGANISM(S): Homo sapiens

PROVIDER: GSE159426 | GEO | 2021/10/01

REPOSITORIES: GEO

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A Genome Wide Association Study Reveals Genetic Predisposition for Bortezomib-Induced Peripheral Neuropathy in Multiple Myeloma by Variation in the PREP1-CBS locus.

Project description:We performed a genome-wide association study using Affymetrix HD-SNP arrays 6.0 to identify risk variants for developing bortezomib-induced peripheral neuropathy (BiPN) in 469 multiple myeloma (MM) patients who received bortezomib-dexamethasone (VD) induction therapy prior to autologous stem-cell transplantation (ASCT) and conducted validation in an independent cohort of 114 MM patients. We identified one previously unreported gene locus associated with BiPN at 21q22.3 (rs2839629, PKNOX1; OR = 1.89, P= 6.47 x 10-7). PKNOX1 is known to regulate expression of MCP-1, a potent mediator of chemotherapy-induced peripheral neuropathy. rs2839629 is in strong linkage disequilibrium (LD, r2 = 0.87) with rs915854, localized 6.5kb centromeric to CBS encoding an endogenous H2S-producing enzyme. CBS-H2S signalling pathway is implicated in the pathogenesis of a variety of neurodegenerative and inflammatory disorders, and specifically in neuropathy models. Our data provide conclusive evidence for genetic susceptibility to BiPN in MM and new potential targets in neuro-protective strategies of treatment.

2016-11-23 | GSE65777 | GEO

XPO1 is a critical player for Bortezomib resistance in Multiple Myeloma: A quantitative proteomic approach

Project description:Among the blood cancers, 13% mortality is caused by Multiple myeloma (MM) type of haematological malignancy. In spite of therapeutic advances in chemotherapy treatment, still MM remains an incurable disease is mainly due to emergence of chemoresistance. At present time, FDA approved bortezomib is the first line drug for MM treatment. However, like other chemotherapy, MM patients are acquiring resistance against bortezomib. The present study aims to identify and validate bortezomib resistant protein targets in MM using iTRAQ and label free quantitative proteomic approaches. 125 differentially expressed proteins were commonly found in both approaches with similar differential expression pattern. XPO1 protein was selected for further validation as its significant high expression was observed in both iTRAQ and label free analysis. Bioinformatic analysis of these common differentially expressed proteins showed a clear cluster of proteins such as SMC1A, RCC2, CSE1, NUP88, NUP50, TPR, HSPA14, DYNLL1, RAD21 and RANBP2 being associated with XPO1. Functional studies like cell count assay, flow cytometry assay and soft agar assay proved that XPO1 knock down in RPMI 8226R cell line results in re-sensitization to bortezomib drug

2019-09-09 | PXD013859 | Pride

Expression profile of MM.1S tumors folloiwing treatment with bortezomib

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2019-03-27 | GSE123637 | GEO

Machine learning-assisted classification of responders and non-responders to bortezomib treatment regimens PAD and VCD using new experimental dataset of 58 multiple myeloma RNA sequencing profiles

Project description:Machine learning-assisted classification of responders and non-responders to bortezomib treatment regimens PAD and VCD using new experimental dataset of 58 multiple myeloma RNA sequencing profiles

| PRJNA668906 | ENA

Genome wide association study on neuropathy in multiple myeloma

Project description:Performing GWAS on multiple myeloma in relation to the development of the toxicity neuropathy. This set was used as validation set. We performed a genome-wide association study using Affymetrix HD-SNP arrays 6.0 to identify risk variants for developing bortezomib-induced peripheral neuropathy (BiPN) in 469 multiple myeloma (MM) patients who received bortezomib-dexamethasone therapy prior to autologous stem-cell transplantation and conducted validation in an independent cohort of 116 MM patients. We identified one previously unreported BiPN risk locus at 21q22.3 (rs2839629, PKNOX1; OR = 0.53, 95% CI: [0.40-0.69]). PKNOX1 is known to regulate MCP-1, a potent mediator of chemotherapy-induced peripheral neuropathy. rs2839629 is in strong linkage disequilibrium ( r2 = 0.87) with rs915854, localized 6.5kb centromeric to CBS encoding endogenous H2S-producing enzyme. CBS-H2S signalling pathway is implicated in the pathogenesis of a variety of neurodegenerative and inflammatory disorders, and specifically in neuropathy models. Our data provide conclusive evidence for genetic susceptibility to BiPN in MM and new potential targets in neuro-protective strategies of treatment.

2016-06-01 | GSE66903 | GEO

Acupuncture Synergized With Bortezomib Improves Survival of Multiple Myeloma Mice via Decreasing Metabolic Ornithine

Project description:Multiple myeloma (MM) is a hematological malignancy worldwide in urgent need for novel therapeutic strategies. Since Velcade (bortezomib) was approved for the treatment of relapsed/refractory MM in 2003, we have seen considerable improvement in extending MM patient survival. However, most patients are fraught with high recurrence rate and incurability. Acupuncture is known for alleviating patient symptoms and improving the quality of life, but it is not well investigated in MM, especially in combination with bortezomib. In this study, we employed LC-MS and UHPLC-MS together with bioinformatics methods to test blood samples from 5TMM3VT MM murine model mice with four different treatments (control (C) group, bortezomib (V) treatment group, acupuncture (A) group and combined (VA) group). MM mice in group VA had longer survival time than mice in group A or group V. Joint pathway analysis indicated the underlying arginine and proline metabolism pathway among the 32 significantly decreased metabolites in group VA. CCK-8 assay and in vivo experiments validated that ornithine, the metabolite of arginine, promoted MM cell proliferation. In addition, gene expression omnibus (GEO) database analysis suggested that MM patients with higher ornithine decarboxylase 1 (ODC1) expression were evidently associated with poor overall survival. In summary, this study demonstrates the synergistic effects of acupuncture and bortezomib on extending the survival of MM model mice and provides potential therapeutic targets in the treatment of MM.

2022-02-21 | MTBLS3487 | MetaboLights

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

Identification of genes associated with bortezomib-based treatment in multiple myeloma patients through bone marrow single-cell RNA-Seq

Project description:In this study, we performed scRNA-seq analyses of bone marrow mononuclear cells (BM-MNCs) in patients with MM receiving bortezomib-based treatments to investigate following questions; (i) the compositional differences in BM-MNCs between normal control and MM patients, and between good and poor responder groups, and (ii) the genes and the cell-to-cell communication networks associated with the treatment responsiveness.

2022-09-14 | GSE189460 | GEO

Carfilzomib-induced reticulocytosis in patients with multiple myeloma is caused by impaired terminal erythroid maturation

Project description:Proteasome inhibition constitutes a cornerstone of multiple myeloma (MM) treatment, with bortezomib, carfilzomib and ixazomib approved for clinical use. We observed a consistent and highly significant increase in the reticulocyte count during treatment with carfilzomib-based regimens in patients with relapsed MM, an observation not made in a matched cohort of bortezomib-treated patients. As this increased reticulocytosis was neither associated with elevated hemoglobin levels nor with hemolysis, we subsequently performed in vitro experiments to unravel the underlying mechanisms of this clinical observation. While carfilzomib did not affect erythroid differentiation of CD34+ hematopoietic progenitor cells, both continuous and pulse exposure to carfilzomib significantly impaired terminal maturation of purified primary reticulocytes towards erythrocytes. These results indicate that carfilzomib significantly impairs terminal erythroid maturation, independent of erythroid commitment, expansion or differentiation. Our results report the first pharmacologically induced delay in erythroid maturation as a mechanism for carfilzomib-induced reticulocytosis in MM patients. Quantitative proteomics using LC-MS/MS were performed to assess whether carfilzomib treatment alters the protein composition of reticulocytes

2020-02-20 | PXD014353 | Pride

RNA-Seq of newly diagnosed patients in the PADIMAC study leads to a bortezomib/lenalidomide decision signature

Project description:Improving outcomes in multiple myeloma will not only involve development of new therapies, but better use of existing treatments. We performed RNA sequencing (RNA-Seq) on samples from newly diagnosed patients enrolled into the phase II PADIMAC study. Using an empirical Bayes approach and synthetic annealing, we developed and trained a seven-gene signature to predict treatment outcome. We tested the signature on independent cohorts treated with bortezomib- and lenalidomide-based therapies. The signature was capable of distinguishing which patients would respond better to which regimen. In the CoMMpass dataset, patients who were treated correctly according to the signature had a better progression-free and overall survival than those who were not. Indeed, the outcome for these correctly treated patients was non-inferior to those treated with combined bortezomib, lenalidomide, and dexamethasone (VRD). PADIMAC: Bortezomib, Adriamycin and Dexamethasone (PAD) therapy for previously untreated patients with multiple myeloma: Impact of minimal residual disease (MRD) in patients with deferred ASCT (autologous stem cell transplant)

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