scholarly journals Coinhibitory molecule PD-1 as a potential target for the immunotherapy of multiple myeloma

Leukemia ◽  
2013 ◽  
Vol 28 (5) ◽  
pp. 993-1000 ◽  
Author(s):  
D Atanackovic ◽  
T Luetkens ◽  
N Kröger
Keyword(s):  
Multiple Myeloma ◽  
Potential Target

C-met Receptor as a Potential Target for the Treatment of Patients with Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3395-3395
Author(s):  
Marcin Majka ◽  
Artur Jurczyszyn ◽  
Anna Zebzda ◽  
Wojciech Czogala ◽  
Ewa Lesko ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Lines ◽  
Protein Level ◽  
Bone Marrow Cells ◽  
Response To Therapy ◽  
Poor Responders ◽  
Met Receptor ◽  
Potential Target ◽  
Marrow Cells

Abstract Despite progress in the treatment of Multiple Myeloma (MM), it is still an incurable disease with average survival of 3–4 years. Because MM is often resistant to conventional therapies, new treatment strategies are necessary. The presence of elevated HGF (Hepatocytic Grow Factor) expression has been well documented in multiple myeloma. The c-met oncogene has been shown to be present in MM cell lines at the mRNA and protein level. Some data suggested that this axis could be responsible for proliferation and inhibition of apoptosis in MM cells. In this study we have analyzed c-met expression in 15 patients with (MM) before and after treatment. Seven of these pts responded well and eight pts responded poorly to the employed therapy. All 15 pts were c-met positive before therapy. Bone marrow cellularity of patients who responded well was 76% before (range: 10% – 100%) and 46% after treatment (range: 40% – 60%). In this group plasmocyte infiltration of bone marrow consisted of 59% before (range: 10% – 80%) and 9% after chemotherapy (range: 0% – 20%). Five of them had undetectable c-met positive cells among bone marrow cells after treatment. In the group of poor responders cellularity of bone marrow was 40% (range: 20% – 70%) before treatment and 46% (range: 20% – 70%) after therapy. Plasmocytes consisted of 20% (range: 10% – 50%) of bone marrow cells before and 44% (range: 10% – 90%) after treatment. All patients in this group had cells positive for c-met receptor after therapeutic regiment. This results suggested that c-met-HGF axis might be a good target for alternative therapy in MM. We looked for potential therapeutics that interferes with this axis and we found that geldanamycin (GA) has been shown to decrease expression of c-met at the protein level in several different cell types. Using inhibitors that belongs to geldanamycin family (GA, 17AAG and 17DMAG) we treated MM cell lines and primary sample. We found that these molecules strongly inhibited expression of c-met in both MM cell lines and patients sample as assessed by western blot analysis. We also tested the influence of these inhibitors on proliferation of MM cells. We found that 100nM dose of GA and 17DMAG inhibited growth of MM cell lines by 80% and 100nM dose of 17AAG inhibited growth of these cells by 20%. Primary cells were more resistant to treatment but we still obtained 30% inhibition with GA and 17DMAG. 17AAG was ineffective and proliferation decreased by less than 10%. Grow inhibition was probably not only due to c-met-HGF axis blockade because these molecules also inhibit other proteins (AKT, RAF). In our experiments we have shown that the level of c-met expression correlates with response to therapy. Patients who respond well had substantially decreased number of c-met positive plasmocytes after chemotherapy in comparison to poor responders. We have also showed that drugs that block c-met-HGF axis could be used in treatment of MM. These drugs could potentially inhibit cells proliferation, increase apoptosis and disrupt MM cells interaction with bone marrow environment. Based on these data we postulate that the c-met receptor is a potential target for MM therapy especially in patients who do not respond to the first line of treatment.

AURKA is a potential target for multiple myeloma therapy

2017 ◽  
Vol 1 (3) ◽  
pp. 47-51
Author(s):  
Ting Lu ◽  
◽  
Chunyan Gu
Keyword(s):  
Multiple Myeloma ◽  
Potential Target

scholarly journals A Novel Therapy-Resistance Transcriptional Signature Based on Single Cell Analysis in Kydar Clinical Trial

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 19-20
Author(s):  
Yael C Cohen ◽  
Mor Zada ◽  
Shuang-Yin Wang ◽  
Chamutal Bornstein ◽  
Eyal David ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
Single Cell ◽  
Cell Lines ◽  
Proteasome Inhibitors ◽  
Therapy Resistance ◽  
Newly Diagnosed ◽  
Rna Seq ◽  
Transcriptional Signature ◽  
Potential Target

Substantial progress in the treatment of Multiple Myeloma (MM) extends survival for many patients (Pts), though most Pts eventually relapse and become therapy refractory. Patients with induction resistant multiple myeloma (IRMM), either primary refractory or early (≤18 months) relapse, have a particularly compromised survival. New treatment strategies and molecular biomarkers for patient stratification and effective clinical care are needed. We previously reported outcomes of KYDAR (NCT04065789) single-arm prospective clinical trial, in which pts primary resistant to a bortezomib-based induction achieved high rates of durable responses when treated with carfilzomib/daratumumab/lenalidomide/dexamethasone (Cohen YC et al. Blood (2019) 134 (Suppl 1): 982). We applied comprehensive single cell RNA-seq analysis of plasma cells (PCs) obtained from longitudinal bone marrow aspirate samples, taken from KYDAR participants (n=34), compared to newly diagnosed MM Pts (n=15) and to healthy controls (n=11). We discovered a novel MM resistance signature differentially expressed between IRMM and newly diagnosed MM groups. This "gene module is enriched for several pathways that were perturbed in the IRMM Pts, including mitochondrial stress genes, the ER and UPR pathway, and the proteasome machinery. Furthermore, differential gene expression analysis between KYDAR responders and non-responders unveil potentially druggable escape mechanisms. These include upregulation of genes associated with immune regulation, proteasome, apoptotic and ER-stress pathways, e.g. Cyclophilin A (PPIA) creating an elaborated signature and potential target list of pathways and escape mechanisms from a highly potent quadruple therapy. This signature includes many novel genes which were not previously described in the context of MM (Fig 1A). Here we report external validation of this novel resistance signature among 908 MM Pts in the MMRF CoMMpass dataset. We found that our genes signature expression follows a normal distribution with no apparent sub-populations in naïve patients, but when examining Pts after multiple relapses, we detected gradient increase in our signature with a clear bi-model distribution (Fig. 1B). The prevalence of high module-1 expression was 5% in newly diagnosed Pts vs 14% in Pts in 3rd or subsequent relapse (p<0.001). Survival analysis on MMRF "module 1 high" (module 1 score > 200) Pts (n = 68) compared with the rest of the population (n = 711) revealed a striking hazard-ratio of 3.9 (2.22 - 6.87) with p-value = 4.57x10-17 (Fig 1C). Module-1 was highly predictive of treatment outcome in KYDAR trials, beyond FISH cytogenetics (Fig 1D). We hypothesized that PPIA may function as a protective resistance gene in MM malignant cells, by accelerating protein folding pathways and reducing stress associated to proteasome inhibitors. In order to test whether PPIA is merely a marker for highly resistant patients or has a causal role in MM resistance to proteasome inhibitors, we used Cyclosporine A (CsA), a known inhibitor of PPIA, in a series of in vitro experiments, to explore it's potential synergy with carfilzomib, a proteasome inhibitor, on RPMI-8226 and U266B MM cell lines, expressing high levels of PPIA. Using MTS proliferation assay, we found that the combined CsA and carfilzomib therapy was significantly more effective than carfilzomib alone. Apoptosis as measured by Propidium Iodide, DAPI and Annexin V FITC staining, was dramatically increased in the combination therapy setting compared to carfilzomib or CsA monotherapy (Fig 1E). In summary, our study defines a roadmap for combining single cell RNA-seq profiling with clinical trials. We reveal and externally-validate a novel transcriptional signature for therapy resistance. We show inhibition of PPIA, a potential target identified, by CsA, overcomes relative resistance of MM cell lines to carfilzomib. We anticipate that such studies will significantly improve the ability to define mechanism of action of treatment, molecularly characterize the Pts that may benefit from the treatment, and reveal potential novel targets. Disclosures Tadmor: AbbVie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Medison: Consultancy, Speakers Bureau; Neopharm: Consultancy, Speakers Bureau; 6. Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Consultancy, Speakers Bureau.

The MMSET Gene Contributes to the Growth, Adhesion, and Tumorigencitiy of t(4;14) Multiple Myeloma Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2636-2636
Author(s):  
Josh Lauring ◽  
Abde M. Abukhdeir ◽  
Hiroyuki Konishi ◽  
Joseph P. Garay ◽  
John P. Gustin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Colony Formation ◽  
Poor Prognosis ◽  
Target Genes ◽  
Critical Role ◽  
Growth Factor Receptor ◽  
Tumor Formation ◽  
Potential Target ◽  
Cycle Arrest

Abstract Multiple myeloma (MM) is an incurable hematological malignancy characterized by recurrent chromosomal translocations. The t(4;14)(p16;q32) is associated with the worst prognosis of any patient subgroup in MM, although the basis for this poor prognosis is unknown. The t(4;14) is unusual in that it involves two potential target genes on chromosome 4: fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain (MMSET). MMSET is universally over-expressed in t(4;14) MM, whereas FGFR3 expression is lost in one third of cases, suggesting a role for MMSET in myeloma pathogenesis. Nonetheless, the role of MMSET in t(4;14) MM has remained unclear. Here we demonstrate a role for MMSET in t(4;14) MM cells. Using homologous recombination-mediated gene targeting, we disrupted the N-terminal and full-length isoforms of MMSET in t(4;14)+ KMS-11 MM cells. Disruption of the translocated MMSET allele revealed that this allele accounts for most of the MMSET transcription in t(4;14) MM cells. Accordingly, selective targeting of the translocated allele, but not the non-translocated allele, led to reduced colony formation in methylcellulose and reduced tumor formation in nude mouse xenografts. Down-regulation of MMSET expression in t(4;14) MM cell lines by stable RNA interference (RNAi) led to a slower growth in liquid culture, a significant reduction in colony formation in methylcellulose, and decreased tumorigenicity in vivo. Additionally, MMSET knockdown led to partial cell cycle arrest of adherent MM cells and reduced the ability of MM cells to adhere to extracellular matrix. Cells with targeted disruption or knockdown of MMSET exhibited changes in expression levels of potential target genes, including several adhesion molecules. These results provide the first direct evidence that translocation-mediated overexpression of MMSET plays a critical role in t(4;14) MM and suggest that therapies targeting this gene could impact this particular subset of poor-prognosis patients.

scholarly journals Prevention Is the Best Treatment: The Case for Understanding the Transition from Monoclonal Gammopathy of Undetermined Significance to Myeloma

2018 ◽  
Vol 19 (11) ◽  
pp. 3621 ◽  
Author(s):  
Michael Tomasson ◽  
Mahmoud Ali ◽  
Vanessa De Oliveira ◽  
Qian Xiao ◽  
Yogesh Jethava ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Gammopathy ◽  
Plasma Cells ◽  
Advanced Disease ◽  
Potential Target ◽  
Prevention Therapy ◽  
Undetermined Significance

Multiple myeloma is an invariably fatal cancer of plasma cells. Despite tremendous advances in treatment, this malignancy remains incurable in most individuals. We postulate that strategies aimed at prevention have the potential to be more effective in preventing myeloma-related death than additional pharmaceutical strategies aimed at treating advanced disease. Here, we present a rationale for the development of prevention therapy and highlight potential target areas of study.

P-Selectin Glycoprotein Ligand-1 as a Potential Target for Humoral Immunotherapy of Multiple Myeloma (Supplementry Material)

2009 ◽  
Vol 9 (5) ◽  
pp. 617-625 ◽  
Author(s):  
C. Tripodo ◽  
A. Florena ◽  
P. Macor ◽  
A. Di Bernardo ◽  
R. Porcasi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Potential Target

scholarly journals Whole genome CRISPR screening identifies TOP2B as a potential target for IMiD sensitization in multiple myeloma

Haematologica ◽  
2020 ◽  
Author(s):  
Matteo Costacurta ◽  
Stephin J Vervoort ◽  
Simon J Hogg ◽  
Benjamin P Martin ◽  
Ricky W Johnstone ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Whole Genome ◽  
Potential Target

Not available.

Cancer Testis Antigen, Ropporin, Is a Potential Target for Multiple Myeloma Immunotherapy

2011 ◽  
Vol 34 (6) ◽  
pp. 490-499 ◽  
Author(s):  
Maurizio Chiriva-Internati ◽  
Leonardo Mirandola ◽  
Yuefei Yu ◽  
Marjorie R. Jenkins ◽  
Rosalba Gornati ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cancer Testis Antigen ◽  
Potential Target ◽  
Cancer Testis

scholarly journals Aberrant Expression of Mir-20a in Serum Exosomes of Multiple Myeloma Lead Abnormal Expression of HIF-1 Signaling Pathway Related Proteins

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 43-43
Author(s):  
Zhiyao Zhang ◽  
Huixing Zhou ◽  
Chuanying Geng ◽  
Wen Gao ◽  
Wenming Chen
Keyword(s):  
Multiple Myeloma ◽  
Differential Expression ◽  
Signaling Pathway ◽  
Microarray Analysis ◽  
Healthy Controls ◽  
Healthy Individuals ◽  
Aberrant Expression ◽  
Potential Target ◽  
Abnormal Expression ◽  
Related Proteins

Objective To determine the abnormal expression of miRNA in plasma exosomes of patients with multiple myeloma (MM) and its effect on the expression of HIF signaling pathway related proteins. Methods Microarray analysis was performed on the exosomal miRNA analysis of 12 MM patients to determine how it might participate in MM. Then a co-expression network was performed to discover the potential role of miRNAs in regulating tumorigenesis and disease progression of MM. The expression of miR-20a in the exosomes of 48 MM patients was detected and the potential target genes were verified. Results Differential expression of 43 miRNAs was observed in exosomes of multiple myeloma (MM) patients compared to healthy individuals. Among them, 7 miRNAs were significantly up-regulated in patients with multiple myeloma, and 35 miRNAs were significantly decreased compared with healthy controls. The results of microarray analysis showed that the seven miRNAs up-regulated in MM exosomes were mainly involved in NF-κB signaling, tumor necrosis factor-mediated signaling pathway regulation while 37 down-regulated miRNAs are mainly involved in HIF-1 signaling pathway, vascular development, cell adhesion. Decreased expression of miR-20a was associated with MM aggressiveness in the MM cohort compared with healthy individuals. We identified HIF-1 signaling pathway related proteins SENP1 and sumo as a potential target gene of miR-20a which were upregulation in MM. Conclusion The microarray chip confirmed the differential expression of miRNA in plasma exosomes of patients with myeloma and healthy controls. Abnormally expressed miRNAs may be involved in the occurrence and development of tumors. These results may provide further evidence for exosomes as novel biomarkers for predicting MM recurrence. Disclosures No relevant conflicts of interest to declare.

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