scholarly journals MCT1 is a Predictive Marker for Lenalidomide Maintenance Therapy in Multiple Myeloma

2021 ◽  
Author(s):  
Jacob Stroh ◽  
Anja Seckinger ◽  
Michael Heider ◽  
Martina Rudelius ◽  
Ruth Eichner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Maintenance Therapy ◽  
Xenograft Model ◽  
Predictive Marker ◽  
Bortezomib Treatment ◽  
High Gene Expression ◽  
Cd147 Expression ◽  
High Gene

Biomarkers that predict response to lenalidomide maintenance therapy in patients with multiple myeloma (MM) have remained elusive. We have shown that IMiDs exert anti-MM activity via destabilization of MCT1 and CD147. Here, samples of 654 patients receiving lenalidomide (n=455), thalidomide (n=98) or bortezomib (n=101) maintenance were assessed using gene expression profiling and RNA-sequencing, followed by correlation of MCT1 and CD147 expression with progression-free (PFS) and overall survival (OS) data. Patients with high gene expression levels of MCT1 showed significantly reduced PFS (31.9 vs. 48.2 months in MCT1high vs. MCT1low, P=.03) and OS (75.9 months vs. not reached (NR) months in MCT1high vs. MCT1low; P=.001) in case of lenalidomide maintenance, whereas MCT1 expression had no significant impact on PFS or OS in patients with bortezomib maintenance. We validated the predictive role of MCT1 for IMiD-based maintenance in an independent cohort of patients receiving thalidomide (OS 83.6 months vs. NR in MCT1high vs. MCT1low; P=.03). Functional validation showed that MCT1 overexpression in human MM cell lines significantly reduced efficacy of lenalidomide, while no change was observed upon bortezomib treatment, both in vitro and in an MM xenograft model. Together, we establish MCT1-expression as a predictive marker for response to lenalidomide-based maintenance treatment.

scholarly journals MCT1 As Molecularly Validated Predictive Marker for Lenalidomide-Maintenance Therapy in Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3187-3187
Author(s):  
Jacob Stroh ◽  
Anja Seckinger ◽  
Michael Heider ◽  
Ruth Eichner ◽  
Martina Emde ◽  
...  
Keyword(s):  
Gene Expression ◽  
Board Of Directors ◽  
Research Funding ◽  
Maintenance Treatment ◽  
Xenograft Model ◽  
Predictive Marker ◽  
High Dose ◽  
Advisory Committees

Introduction: Lenalidomide-based maintenance therapy is the currently approved standard of care for multiple myeloma (MM) patients after high-dose melphalan and autologous stem cell transplantation (HD-Mel), which significantly prolongs progression-free (PFS) and overall survival (OS). For patients with del17p bortezomib based maintenance treatment is considered overcoming adverse prognosis of this aberration. Predictive markers of response to lenalidomide maintenance have remained elusive. We have previously shown that IMiDs exert their anti-MM activity via destabilization of MCT1 and CD147 and combined overexpression reduces response to lenalidomide-treatment in vitro and in an in vivo MM xenograft model (Eichner et al. Nature Medicine 2016). Methods: CD138-purified myeloma cell samples of 654 patients receiving high-dose melphalan therapy and autologous stem cell transplantation and either bortezomib (n=101), thalidomide (n=98) or lenalidomide (n=455) maintenance treatment were assessed by gene expression profiling (GEP) using U133 2.0 plus DNA microarrays, 316 by RNA-sequencing (RNA-seq). Expression of CD147 and MCT1 were assessed and correlated with PFS and OS data. Gene expression based risk scores, including UAMS70-gene, Rs-score and gene expression based proliferation index were assessed alongside routine iFISH-analysis. Survival curves and median time to progression were computed with nonparametric survival estimates for censored data using the Kaplan-Meier method. Difference between the curves were tested using the G-rho Log-rank test. Landmark analysis was performed by defining an alternative start point (landmark) at 12 months. In vitro, CD147 and MCT1 were lentivirally overexpressed in MM1S cells, which were subjected to lenalidomide or bortezomib treatment and proliferation analysis. Xenografted MM-tumors were followed by 18FDG-PET and analyzed by immunohistochemistry. Results: Patients with high gene expression levels of MCT1 showed significantly reduced PFS (31.9 vs. 48.2months in MCT1high vs. MCT1low,P=.03) and OS (75.9 months vs. not reached (NR) months in MCT1high vs. MCT1low; P=.001) in case of lenalidomide maintenance. Likewise, patients with thalidomide maintenance showed reduced PFS (34.8 vs. 43.7 months in MCT1high vs. MCT1low, P=.23) and significantly shorter OS (83.6 months vs. not reached (NR) months in MCT1high vs. MCT1low;P=.03). For bortezomib based maintenance, MCT1 expression had no significant impact on PFS (39.8 months vs. 32.6 months in MCT1high vs. MCT1low) and OS (125.8 months vs. 129.8 months in MCT1high vs. MCT1low). No association with other prognostic factors was found. As still differences between MCT1high vs. MCT1lowexpression myeloma cells might be attributed to undiscerned molecular factors and for functional validation, we lentivirally overexpressed CD147 and MCT1 in human myeloma cell lines. Overexpression of MCT1 significantly reduced cytotoxicity of lenalidomide, while no change was observed in MM cells treated with bortezomib. We subsequently validated our results in vivo. Functional investigations in the mechanism of MCT1 impact on cellular survival are ongoing. Conclusion: Taken together MCT1 expression as potential predictive marker for response to IMiD-based maintenance treatment. Both PFS and OS were significantly reduced in patients with high gene expression levels of MCT1. In vitro and in vivo (xenograft model), MCT1 overexpression reduced sensitivity to lenalidomide unlike bortezomib treatment. Disclosures Salwender: Bristol-Myers Squibb: Honoraria, Other: Travel or accommodations; Janssen Cilag: Honoraria, Other: Travel or accommodations; AbbVie: Honoraria; Celgene: Honoraria, Other: Travel or accommodations; Sanofi: Honoraria, Other: Travel or accommodations; Takeda: Honoraria, Other: Travel or accommodations; Amgen: Honoraria, Other: Travel or accommodations. Bertsch:Sanofi: Other: travel support; Celgene: Other: travel support. Goldschmidt:Chugai: Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Molecular Partners: Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Research Funding; Dietmar-Hopp-Stiftung: Research Funding; John-Hopkins University: Research Funding; John-Hopkins University: Research Funding; MSD: Research Funding; Mundipharma: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Weisel:Takeda: Consultancy, Honoraria; GSK: Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Juno: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria. Scheid:Celgene: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria. Bassermann:Celgene: Consultancy, Research Funding.

scholarly journals In Vitro Cell Sensitivity to Palytoxin Correlates with High Gene Expression of the Na+/K+-ATPase β2 Subunit Isoform

2020 ◽  
Vol 21 (16) ◽  
pp. 5833
Author(s):  
Marco Pelin ◽  
Gabriele Stocco ◽  
Chiara Florio ◽  
Silvio Sosa ◽  
Aurelia Tubaro
Keyword(s):  
Gene Expression ◽  
Interquartile Range ◽  
Toxic Effects ◽  
Maximum Effect ◽  
Molecular Evidence ◽  
Expression Ratio ◽  
Assay Sensitivity ◽  
High Gene Expression ◽  
High Gene

The marine polyether palytoxin (PLTX) is one of the most toxic natural compounds, and is involved in human poisonings after oral, inhalation, skin and/or ocular exposure. Epidemiological and molecular evidence suggest different inter-individual sensitivities to its toxic effects, possibly related to genetic-dependent differences in the expression of Na+/K+-ATPase, its molecular target. To identify Na+/K+-ATPase subunits, isoforms correlated with in vitro PLTX cytotoxic potency, sensitivity parameters (EC50: PLTX concentration reducing cell viability by 50%; Emax: maximum effect induced by the highest toxin concentration; 10−7 M) were assessed in 60 healthy donors’ monocytes by the MTT (methylthiazolyl tetrazolium) assay. Sensitivity parameters, not correlated with donors’ demographic variables (gender, age and blood group), demonstrated a high inter-individual variability (median EC50 = 2.7 × 10−10 M, interquartile range: 0.4–13.2 × 10−10 M; median Emax = 92.0%, interquartile range: 87.5–94.4%). Spearman’s analysis showed significant positive correlations between the β2-encoding ATP1B2 gene expression and Emax values (rho = 0.30; p = 0.025) and between Emax and the ATP1B2/ATP1B3 expression ratio (rho = 0.38; p = 0.004), as well as a significant negative correlation between Emax and the ATP1B1/ATP1B2 expression ratio (rho = −0.30; p = 0.026). This toxicogenetic study represents the first approach to define genetic risk factors that may influence the onset of adverse effects in human PLTX poisonings, suggesting that individuals with high gene expression pattern of the Na+/K+-ATPase β2 subunit (alone or as β2/β1 and/or β2/β3 ratio) could be highly sensitive to PLTX toxic effects.

scholarly journals Targeting NSD2-mediated SRC-3 liquid–liquid phase separation sensitizes bortezomib treatment in multiple myeloma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jing Liu ◽  
Ying Xie ◽  
Jing Guo ◽  
Xin Li ◽  
Jingjing Wang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Phase Separation ◽  
Liquid Phase ◽  
Liquid Phase Separation ◽  
Acquired Drug Resistance ◽  
Bortezomib Treatment ◽  
Liquid Liquid Phase Separation

AbstractDevelopment of chemoresistance is the main reason for failure of clinical management of multiple myeloma (MM), but the genetic and epigenetic aberrations that interact to confer such chemoresistance remains unknown. In the present study, we find that high steroid receptor coactivator-3 (SRC-3) expression is correlated with relapse/refractory and poor outcomes in MM patients treated with bortezomib (BTZ)-based regimens. Furthermore, in immortalized cell lines, high SRC-3 enhances resistance to proteasome inhibitor (PI)-induced apoptosis. Overexpressed histone methyltransferase NSD2 in patients bearing a t(4;14) translocation or in BTZ-resistant MM cells coordinates elevated SRC-3 by enhancing its liquid–liquid phase separation to supranormally modify histone H3 lysine 36 dimethylation (H3K36me2) modifications on promoters of anti-apoptotic genes. Targeting SRC-3 or interference of its interactions with NSD2 using a newly developed inhibitor, SI-2, sensitizes BTZ treatment and overcomes drug resistance both in vitro and in vivo. Taken together, our findings elucidate a previously unrecognized orchestration of SRC-3 and NSD2 in acquired drug resistance of MM and suggest that SI-2 may be efficacious for overcoming drug resistance in MM patients.

scholarly journals SMAD1 as a biomarker and potential therapeutic target in drug-resistant multiple myeloma

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Jian Wu ◽  
Min Zhang ◽  
Omar Faruq ◽  
Eldad Zacksenhaus ◽  
Wenming Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Therapeutic Target ◽  
Biological Activities ◽  
Xenograft Model ◽  
Myeloma Cell ◽  
Soft Agar ◽  
Drug Resistant ◽  
Migration Assay

Abstract Background SMAD1, a central mediator in TGF-β signaling, is involved in a broad range of biological activities including cell growth, apoptosis, development and immune response, and is implicated in diverse type of malignancies. Whether SMAD1 plays an important role in multiple myeloma (MM) pathogenesis and can serve as a therapeutic target are largely unknown. Methods Myeloma cell lines and primary MM samples were used. Cell culture, cytotoxicity and apoptosis assay, siRNA transfection, Western blot, RT-PCR, Soft-agar colony formation, and migration assay, Chromatin immunoprecipitation (Chip), animal xenograft model studies and statistical analysis were applied in this study. Results We demonstrate that SMAD1 is highly expressed in myeloma cells of MM patients with advanced stages or relapsed disease, and is associated with significantly shorter progression-free and overall survivals. Mechanistically, we show that SMAD1 is required for TGFβ-mediated proliferation in MM via an ID1/p21/p27 pathway. TGF-β also enhanced TNFα-Induced protein 8 (TNFAIP8) expression and inhibited apoptosis through SMAD1-mediated induction of NF-κB1. Accordingly, depletion of SMAD1 led to downregulation of NF-κB1 and TNFAIP8, resulting in caspase-8-induced apoptosis. In turn, inhibition of NF-κB1 suppressed SMAD1 and ID1 expression uncovering an autoregulatory loop. Dorsomorphin (DM), a SMAD1 inhibitor, exerted a dose-dependent cytotoxic effect on drug-resistant MM cells with minimal cytotoxicity to normal hematopoietic cells, and further synergized with the proteasomal-inhibitor bortezomib to effectively kill drug-resistant MM cells in vitro and in a myeloma xenograft model. Conclusions This study identifies SMAD1 regulation of NF-κB1/TNFAIP8 and ID1-p21/p27 as critical axes of MM drug resistance and provides a potentially new therapeutic strategy to treat drug resistance MM through targeted inhibition of SMAD1.

scholarly journals Retained Heterodisomy Is Associated with High Gene Expression in Hyperhaploid Inflammatory Leiomyosarcoma

Neoplasia ◽  
2012 ◽  
Vol 14 (9) ◽  
pp. 807-IN5 ◽  
Author(s):  
Karolin H. Nord ◽  
Kajsa Paulsson ◽  
Srinivas Veerla ◽  
Johan Wejde ◽  
Otte Brosjö ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Gene Expression ◽  
High Gene

scholarly journals A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo

Leukemia ◽  
2016 ◽  
Vol 31 (8) ◽  
pp. 1743-1751 ◽  
Author(s):  
S Hipp ◽  
Y-T Tai ◽  
D Blanset ◽  
P Deegen ◽  
J Wahl ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cell ◽  
Plasma Cells ◽  
Ex Vivo ◽  
Xenograft Model ◽  
Selective Lysis ◽  
Bispecific T Cell Engager

Abstract B-cell maturation antigen (BCMA) is a highly plasma cell-selective protein that is expressed on malignant plasma cells of multiple myeloma (MM) patients and therefore is an ideal target for T-cell redirecting therapies. We developed a bispecific T-cell engager (BiTE) targeting BCMA and CD3ɛ (BI 836909) and studied its therapeutic impacts on MM. BI 836909 induced selective lysis of BCMA-positive MM cells, activation of T cells, release of cytokines and T-cell proliferation; whereas BCMA-negative cells were not affected. Activity of BI 836909 was not influenced by the presence of bone marrow stromal cells, soluble BCMA or a proliferation-inducing ligand (APRIL). In ex vivo assays, BI 836909 induced potent autologous MM cell lysis in both, newly diagnosed and relapsed/refractory patient samples. In mouse xenograft studies, BI 836909 induced tumor cell depletion in a subcutaneous NCI-H929 xenograft model and prolonged survival in an orthotopic L-363 xenograft model. In a cynomolgus monkey study, administration of BI 836909 led to depletion of BCMA-positive plasma cells in the bone marrow. Taken together, these results show that BI 836909 is a highly potent and efficacious approach to selectively deplete BCMA-positive MM cells and represents a novel immunotherapeutic for the treatment of MM.

scholarly journals Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1654-1664 ◽  
Author(s):  
Dharminder Chauhan ◽  
Ajita Singh ◽  
Mohan Brahmandam ◽  
Klaus Podar ◽  
Teru Hideshima ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitors ◽  
Xenograft Model ◽  
Er Stress Response ◽  
Synergistic Cytotoxicity ◽  
Proteolytic Activities ◽  
Dose Combination ◽  
Inhibition Of Tumor Growth

AbstractOur recent study demonstrated that a novel proteasome inhibitor NPI-0052 triggers apoptosis in multiple myeloma (MM) cells, and importantly, that is distinct from bortezomib (Velcade) in its chemical structure, effects on proteasome activities, and mechanisms of action. Here, we demonstrate that combining NPI-0052 and bortezomb induces synergistic anti-MM activity both in vitro using MM cell lines or patient CD138+ MM cells and in vivo in a human plasmacytoma xenograft mouse model. NPI-0052 plus bortezomib–induced synergistic apoptosis is associated with: (1) activation of caspase-8, caspase-9, caspase-3, and PARP; (2) induction of endoplasmic reticulum (ER) stress response and JNK; (3) inhibition of migration of MM cells and angiogenesis; (4) suppression of chymotrypsin-like (CT-L), caspase-like (C-L), and trypsin-like (T-L) proteolytic activities; and (5) blockade of NF-κB signaling. Studies in a xenograft model show that low dose combination of NPI-0052 and bortezomib is well tolerated and triggers synergistic inhibition of tumor growth and CT-L, C-L, and T-L proteasome activities in tumor cells. Immununostaining of MM tumors from NPI-0052 plus bortezomib–treated mice showed growth inhibition, apoptosis, and a decrease in associated angiogenesis. Taken together, our study provides the preclinical rationale for clinical protocols evaluating bortezomib together with NPI-0052 to improve patient outcome in MM.

Effect of Auraptene on angiogenesis in Xenograft model of breast cancer

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Mohammad Reza Shiran ◽  
Elham Mahmoudian ◽  
Abolghasem Ajami ◽  
Seyed Mostafa Hosseini ◽  
Ayjamal Khojasteh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Animal Model ◽  
Protein Expression ◽  
Western Blot ◽  
Xenograft Model ◽  
Dependent Manner ◽  
Concentration Dependent Manner

Abstract Objectives Angiogenesis is the most important challenge in breast cancer treatment. Recently, scientists become interesting in rare natural products and intensive researches was performed to identify their pharmacological profile. Auraptene shows helpful effects such as cancer chemo-preventive, anti-inflammatory, anti-oxidant, immuno-modulatory. In this regard, we investigated the anti-angiogenesis effect of Auraptene in in-vitro and in-vivo model of breast cancer. Methods In this study, 4T, MDA-MB-231 and HUVEC cell lines were used. The proliferation study was done by MTT assay. For tube formation assay, 250 matrigel, 1 × 104 HUVEC treated with Auraptene, 20 ng/mL EGF, 20 ng/mL bFGF and 20 ng/mL VEGF were used. Gene expression of important gene related to angiogenesis in animal model of breast cancer was investigated by Real-time PCR. Protein expression of VCAM-1 and TNFR-1 gene related to angiogenesis in animal model of breast cancer was investigated by western-blot. Results Auraptene treatment led to reduction in cell viability of MDA-MB-231 in a concentration-dependent manner. Also, we observed change in the number of tubes or branches formed by cells incubated with 40 and 80 μM Auraptene. Auraptene effect the gene expression of important gene related to angiogenesis (VEGF, VEGFR2, COX2, IFNɣ). Moreover, the western blot data exhibited that Auraptene effect the protein expression of VCAM-1 and TNFR-1. Conclusions Overall, this study shows that Auraptene significantly suppressed angiogenesis via down-regulation of VEGF, VEGFR2, VCAM-1, TNFR-1, COX-2 and up-regulation of IFNγ.

Sign in / Sign up

Export Citation Format

Share Document