scholarly journals Extramedullary multiple myeloma patient derived orthotopic xenograft with high disturbed genome: combined exhaustive molecular and therapeutic studies

2021 ◽  
Author(s):  
Lourdes Farre ◽  
Gabriela Sanz ◽  
Neus Ruiz-Xivillé ◽  
Manuel Castro de Moura ◽  
Juan Francisco Martín Tejera ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Testing ◽  
Cutaneous Lesion ◽  
Multiple Myeloma Patient ◽  
Extramedullary Disease ◽  
Orthotopic Xenograft ◽  
Molecular Events ◽  
Epigenetic Events ◽  
Nsg Mouse

Extramedullary multiple myeloma (EMM) has an overall survival of 6 months and occurs in 20% of multiple myeloma (MM) patients. Genetic and epigenetic mechanisms involved in EMM and the therapeutic role of new agents for MM are not well established. Besides, well characterized preclinical models for EMM are not available. Herein, a patient derived orthotopic xenograft (PDOX) was generated from a patient with an aggressive EMM to study in-depth genetic and epigenetic events and drug responses related to extramedullary disease. A fresh punch of an extramedullary cutaneous lesion was orthotopically implanted in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ(NSG) mouse. The PDOX mimicked histologic and phenotypic features of patient's tumor. Cytogenetic studies revealed a hyperploid genome with multiple genetic poor-prognosis alterations. Copy number alterations were detected in all chromosomes. The IGH translocation t(14;16)(q32;q23)IGH/MAF were already observed at medullary stage and a new one, the t(10;14)(p?11-12;q32), were observed only at extramedullary disease and could be eventually related to EMM progression in this case. Exome sequencing showed 24 high impact SNV and 180 indels. From the genes involved, only TP53 was previously described as a driver in MM. A rather balanced proportion of hyper/hypomethylated sites different to previously reported widespread hypomethylation in MM was also observed. Treatment with lenalidomide, dexamethasone and carfilzomib showed a tumor weight reduction of 90% vs. non-treated tumors while the anti-CD38 antibody Daratumumab showed a reduction of 46%. The generation of PDOX from small EMM biopsy allowed to go in-deep to the molecular events associated to extramedullary disease in combination with drug testing.

scholarly journals Delineating CDK9 Regulated Molecular Events for the Development of Rationally Derived Multiple Myeloma Treatment Strategies

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1598-1598
Author(s):  
Osman Aksoy ◽  
Judith Lind ◽  
Vincent Sunder-Plassmann ◽  
Martin Percherstorfer ◽  
Sonia Vallet ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Tumor Microenvironment ◽  
Tumor Cell ◽  
Treatment Strategies ◽  
Loss Of Function ◽  
Rna Pol Ii ◽  
Pol Ii ◽  
Protein Levels ◽  
Molecular Events

Abstract Background: Despite major advances in multiple myeloma (MM) therapy over the last 2 decades, most patients relapse. The identification of novel targets and the development of derived treatment approaches are therefore urgently needed. Aberrant expression of various cyclin-dependent kinases (CDKs) in solid and hematologic malignancies including MM, results in the loss of proliferative control and enhanced survival. The serine-threonine kinase CDK9, a subunit of pTEFb, in particular, is a major transcriptional regulator of numerous oncogenes. Past studies have suggested CDK9 as a potential therapeutic target in MM. However, CDK9-regulated molecular events in MM are only partly understood. By delineating CDK9-dependent pathophysiologic effects, the present study proposes rationally derived anti-CDK9-containing novel MM treatment strategies to improve patient outcome. Methods: Following expression profiling, CRISPR loss-of-function screens and correlation analyses in MM cell line and patient cells, the regulatory impact of CDK9 on downstream target genes was outlined using genomic as well as pharmacological approaches in 2D/3D MM models of the tumor microenvironment. Functionally, CDK9-regulated molecular effects as well as anti-MM activity of anti-CDK9-containing rationally derived treatment combinations were determined by gene arrays, qPCR, flow cytometry, and western blot, proliferation and survival analyses. Results: Strongly suggested by a significant induction of CDK9 mRNA expression levels progressing from normal plasma cells to cells from patients with MGUS, SMM and MM; siRNA and CRISP loss-of-function screens across various MM cell lines verified their dependency on CDK9. Correlative expression levels indicated a functional role of CDK9 (but not for CDK2 and CDK7) on Mcl-1, cMyc, Mdm2, RNA Pol II, and IRF4, but not other genes (e.g. Bcl-2) in the CCLE as well as CoMMpass and GSE5900/GSE2658 MM patient datasets. Indeed, siRNA-mediated CDK9 silencing decreased protein levels of Mcl-1, cMyc, Mdm2, RNA Pol II, and IRF4, and consequently tumor cell survival. Similarly, the novel, selective CDK9-directed proteolysis-targeting chimera Thal-sns-032 induced a reduction of mRNA/ protein levels of Mcl-1, cMyc, RNA Pol II, but not of other potential targets (e.g. Bcl-2) in a dose- and time-dependent manner. Moreover, Thal-sns-032 reduced Mdm2 and thereby increased p53 protein levels. Consequently, Thal-sns-032 inhibited tumor cell proliferation and survival both in tumor cell- and tumor cell:BMSC co- cultures. Rationally, derived combination strategies of Thal-sns-032 for example with venetoclax, but also other investigational and established MM therapies induced synergistic anti-MM effects within the tumor microenvironment. Conclusion: In summary, by delineating CDK9-regulated molecular events in MM, our studies strongly support the therapeutic role of targeted CDK9-therapy and rationally derive MM combination treatment strategies. Disclosures Vallet: Pfizer: Honoraria; MSD: Honoraria; Roche Pharmaceuticals: Consultancy. Podar: Celgene: Consultancy, Honoraria; Amgen Inc.: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Roche Pharmaceuticals: Research Funding.

Identification of Novel Angiogenic Proteins in Multiple Myeloma Patient-Derived Endothelial Cells Using Proteome-Wide Analysis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2825-2825
Author(s):  
Roberto Ria ◽  
Simona Berardi ◽  
Antonia Reale ◽  
Giulia Di Pietro ◽  
Antonio Basile ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Endothelial Cells ◽  
Intracellular Signaling ◽  
Conflicts Of Interest ◽  
Molecular Targets ◽  
Mitotic Checkpoint ◽  
Multiple Myeloma Patient ◽  
New Targets ◽  
Angiogenic Proteins

Abstract Abstract 2825 Poster Board II-801 Novel technologies are needed to identify new and more efficient biomarkers and improved molecular targets for accurate diagnosis and treatment of multiple myeloma (MM). Proteomics, i.e., the study of proteins and protein pathways involved in disease, is a new dimension in preclinical and clinical development. Preliminary studies in global protein expression of bone marrow endothelial cells (ECs) of patients with MM (MMECs) and ECs from monoclonal gammopathy of undetermined significance (MGUS-MGECs) vs. human umbilical vein endothelial cells (HUVECs), has shown at least 20 proteins differentially expressed in MMECs. The association of monodimensional electrophoresis with MALDI-MS analysis allowed us to identify a series of proteins that are shown to be important biomarkers to differentiate MMECs vs. MGECs and HUVECs, and distinguish different stages in MM progression, i.e., diagnosis, relapse, and refractory disease. These proteins are known to play important roles in cellular functions such as glycolysis (α-enolase and glyceraldehyde-3-phosphate dehydrogenase), cell-cycle regulation (14-3-3 zeta/delta protein, mitotic checkpoint serine/threonine-protein kinase BUB1), apoptosis (annexin V), angiogenesis and metastasis (vimentin, α-filamin) and they might contribute to the adverse evolution of the disease. Preliminary results suggest that the increased expression of α-filamin in ECs from an active desease, refractory desease and stable desease, the upregulation of vimentin in ECs from an active desease and down regulation of annexin VI in ECs from a refractory desease is related to the cell overangiogenic potential, indicate a common machinery involved with the structural organization of the cytoskeleton and with the connection of matrix and cell–cell external signals with the intracellular signaling pathways. On the other hand, changes in the expression of structural proteins (Filamin, vimentin, alpha-actinin), could account, at least in part, for the different morphologies displayed by migrating endothelial cells. In order to understand the role of these proteins in the angiogenic switch, the molecular targets potentially useful in the antiangiogenic treatment of MM were silenced by siRNA experiments and their potential involvement in migration and proliferation was investigated by proliferation, cell adhesion and invasion essays. This study has delineated the functional profile of the proteome of ECs in patients with MM in order to understand some of the mechanisms involved in neovascularisation and progression of MM and to identify new targets useful in the treatment of these patients. Because angiogenesis and lymphangiogenesis actively contribute to cancer progression, future studies to establish the role of these angiogenic proteins in disease may suggest potential new targets for tissue-specific therapies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Treatment Patterns and Clinical Outcomes in High-Risk Multiple Myeloma Patients Carrying the 17p Deletion: A Multi-Center Retrospective Observational Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4510-4510
Author(s):  
Yael Cohen ◽  
Moshe E. Gatt ◽  
Noa Lavi ◽  
Chezi Ganzel ◽  
Hila Magen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Clinical Trials ◽  
High Risk ◽  
Plasma Cells ◽  
Response Rate ◽  
Treatment Patterns ◽  
Extramedullary Disease ◽  
Access Programs

Abstract Introduction Improvement in overall survival (OS) is seen primarily within standard risk Multiple Myeloma (MM), however, high risk MM OS was still around 2-3 years until recently. Del17p is a genomic imbalance which includes deletion of the TP53 locus. It occurs in ~7-10% of MM at diagnosis and is associated with extramedullary disease and is a strong poor prognostic factor. Recently approved novel agents and combinations have demonstrated improved outcomes also in patients with negative cytogenetic features; however, their long term impact remains to be seen. Access to newer agents depends on time of diagnosis as well as availability of clinical trials, access programs and insurance coverage. The goal of this study is to analyze real world data including treatment patterns and outcomes among MM patients carrying 17p deletion, in a retrospective multi-site study. Methods An observational, retrospective, multi-center study. Consecutive patients diagnosed with multiple myeloma in the 8 participating centers in Israel, diagnosed between 1.1.2008 - 3.1.2016 that were proven to carry 17p deletion by means of FISH studies (any % of plasma cells), were identified by searching hospital records including cytogenetic lab records. Data concerning patient demographics, disease characteristics, treatment regimens and clinical endpoints were collected. Results A total of 57 patients carrying 17p deletion of FISH were identified. Patient's characteristics are described in table. Notably, most patients had bone disease; extramedullary disease (EMD) rate was relatively high, as was the presence of additional high risk FISH abnormalities. Most patients received a bortezomib-based induction, over half underwent ASCT. Fifteen (26%) of the patients participated in clinical trials or access programs (or both) (table). Overall response rate (ORR) after induction was 84%, response rate declined in subsequent treatment lines (figure 1). The median follow-up was 21 (range, 4-94) months. Median overall survival (OS) was 43 months; Median Progression free survival (PFS) was 20 months (figure 2A,B). In univariate analysis, presence of extra-medullary disease at diagnosis was associated with worse PFS (7.4 vs. 21.4 months, p=0.05, figure 2C); presence of additional high risk FISH findings also trended towards shorter PFS (13.5 vs 21.4 months, p=0.0569), while age, gender, ISS, %plasma cells, % cells with del17p, time of del17p detection, M-Spike and iFLC levels were not significantly associated with PFS. Among patients with a PFS greater than 6 months, ASCT was associated with a significant improvement in PFS (25.7 vs 9.0 months, p=0.0022 log-rank test) (figure 2D), 4 patients underwent allotransplant, with a median OS of 69 months. Conclusions Our data confirm the poor prognosis of myeloma patients with del17p, in a multi-site observational setting, and an even worse prognosis in the presence of extramedullary disease and additional high-risk FISH features. While ORR after induction is similar to that generally expected in a newly diagnosed myeloma patients, responses are shorter and thus PFS is inferior compared to recently reported upfront bortezomib-based regimens ranging from 30-40+ months. Responses decline further in subsequent lines yet remain non-negligible even in advanced therapeutic lines. Our data support the role of ASCT in these high risk patients, and the potential role of allotransplant in selected patients. High rate of participation in clinical trials and access programs throughout the course of therapy reflects the valued role of newer agents in the management of myeloma patients. Disclosures Avivi: Tel Aviv Sourasky Medical center: Consultancy, Other: consultancy to :BMS Roche.

The role of nuclear factor-[kappa ]B in the biology and treatment of multiple myeloma

2001 ◽  
Vol 28 (6) ◽  
pp. 626-633 ◽  
Author(s):  
James R. Berenson ◽  
Hongjin M. Ma ◽  
Robert Vescio
Keyword(s):  
Multiple Myeloma ◽  
Nuclear Factor Kappa B ◽  
Nuclear Factor ◽  
Nuclear Factor Kappa

CD38 as an immunomodulator in cancer

2020 ◽  
Vol 16 (34) ◽  
pp. 2853-2861
Author(s):  
Yanli Li ◽  
Rui Yang ◽  
Limo Chen ◽  
Sufang Wu
Keyword(s):  
Multiple Myeloma ◽  
Cell Activation ◽  
Human Tissues ◽  
Transmembrane Glycoprotein ◽  
Cell Activation Marker ◽  
Research Findings ◽  
A Cell ◽  
And Function ◽  
Human Molecule

CD38 is a transmembrane glycoprotein that is widely expressed in a variety of human tissues and cells, especially those in the immune system. CD38 protein was previously considered as a cell activation marker, and today monoclonal antibodies targeting CD38 have witnessed great achievements in multiple myeloma and promoted researchers to conduct research on other tumors. In this review, we provide a wide-ranging review of the biology and function of the human molecule outside the field of myeloma. We focus mainly on current research findings to summarize and update the findings gathered from diverse areas of study. Based on these findings, we attempt to extend the role of CD38 in the context of therapy of solid tumors and expand the role of the molecule from a simple marker to an immunomodulator.

scholarly journals The Role of Monoclonal Antibodies in Smoldering and Newly Diagnosed Transplant-Eligible Multiple Myeloma

2020 ◽  
Vol 13 (12) ◽  
pp. 451
Author(s):  
Elena Zamagni ◽  
Paola Tacchetti ◽  
Paola Deias ◽  
Francesca Patriarca
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Immune System ◽  
Survival Outcomes ◽  
Newly Diagnosed ◽  
Cellular Targets ◽  
Recent Introduction

The recent introduction of monoclonal antibodies (MoAbs), with several cellular targets, such as CD-38 (daratumumab and isatuximab) and SLAM F7 (elotuzumab), differently combined with other classes of agents, has significantly extended the outcomes of patients with multiple myeloma (MM) in different phases of the disease. Initially used in advanced/refractory patients, different MoAbs combination have been introduced in the treatment of newly diagnosed transplant eligible patients (NDTEMM), showing a significant improvement in the depth of the response and in survival outcomes, without a significant price in terms of toxicity. In smoldering MM, MoAbs have been applied, either alone or in combination with other drugs, with the goal of delaying the progression to active MM and restoring the immune system. In this review, we will focus on the main results achieved so far and on the main on-going trials using MoAbs in SMM and NDTEMM.

scholarly journals Comparison of the prognostic significance of 5 comorbidity scores and 12 functional tests in a prospective multiple myeloma patient cohort

Cancer ◽  
2021 ◽  
Author(s):  
Sophia Scheubeck ◽  
Gabriele Ihorst ◽  
Katja Schoeller ◽  
Maximilian Holler ◽  
Mandy‐Deborah Möller ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Prognostic Significance ◽  
Functional Tests ◽  
Myeloma Patient ◽  
Multiple Myeloma Patient ◽  
Patient Cohort ◽  
Comorbidity Scores

scholarly journals Transient Receptor Potential C 1/4/5 Is a Determinant of MTI-101 Induced Calcium Influx and Cell Death in Multiple Myeloma

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1490
Author(s):  
Osama M. Elzamzamy ◽  
Brandon E. Johnson ◽  
Wei-Chih Chen ◽  
Gangqing Hu ◽  
Reinhold Penner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Transient Receptor Potential ◽  
Cyclic Peptide ◽  
Calcium Influx ◽  
Acquired Resistance ◽  
Treatment Strategies ◽  
Prognostic Indicators ◽  
Causative Role

Multiple myeloma (MM) is a currently incurable hematologic cancer. Patients that initially respond to therapeutic intervention eventually relapse with drug resistant disease. Thus, novel treatment strategies are critically needed to improve patient outcomes. Our group has developed a novel cyclic peptide referred to as MTI-101 for the treatment of MM. We previously reported that acquired resistance to HYD-1, the linear form of MTI-101, correlated with the repression of genes involved in store operated Ca2+ entry (SOCE): PLCβ, SERCA, ITPR3, and TRPC1 expression. In this study, we sought to determine the role of TRPC1 heteromers in mediating MTI-101 induced cationic flux. Our data indicate that, consistent with the activation of TRPC heteromers, MTI-101 treatment induced Ca2+ and Na+ influx. However, replacing extracellular Na+ with NMDG did not reduce MTI-101-induced cell death. In contrast, decreasing extracellular Ca2+ reduced both MTI-101-induced Ca2+ influx as well as cell death. The causative role of TRPC heteromers was established by suppressing STIM1, TRPC1, TRPC4, or TRPC5 function both pharmacologically and by siRNA, resulting in a reduction in MTI-101-induced Ca2+ influx. Mechanistically, MTI-101 treatment induces trafficking of TRPC1 to the membrane and co-immunoprecipitation studies indicate that MTI-101 treatment induces a TRPC1-STIM1 complex. Moreover, treatment with calpeptin inhibited MTI-101-induced Ca2+ influx and cell death, indicating a role of calpain in the mechanism of MTI-101-induced cytotoxicity. Finally, components of the SOCE pathway were found to be poor prognostic indicators among MM patients, suggesting that this pathway is attractive for the treatment of MM.

scholarly journals Evaluating Targeted Therapies in Ovarian Cancer Metabolism: Novel Role for PCSK9 and Second Generation mTOR Inhibitors

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3727
Author(s):  
Dafne Jacome Sanz ◽  
Juuli Raivola ◽  
Hanna Karvonen ◽  
Mariliina Arjama ◽  
Harlan Barker ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Lipid Metabolism ◽  
Cell Survival ◽  
Drug Testing ◽  
Cancer Metabolism ◽  
Ex Vivo ◽  
Specific Inhibitor ◽  
Low Grade ◽  
Serous Ovarian Cancer

Background: Dysregulated lipid metabolism is emerging as a hallmark in several malignancies, including ovarian cancer (OC). Specifically, metastatic OC is highly dependent on lipid-rich omentum. We aimed to investigate the therapeutic value of targeting lipid metabolism in OC. For this purpose, we studied the role of PCSK9, a cholesterol-regulating enzyme, in OC cell survival and its downstream signaling. We also investigated the cytotoxic efficacy of a small library of metabolic (n = 11) and mTOR (n = 10) inhibitors using OC cell lines (n = 8) and ex vivo patient-derived cell cultures (PDCs, n = 5) to identify clinically suitable drug vulnerabilities. Targeting PCSK9 expression with siRNA or PCSK9 specific inhibitor (PF-06446846) impaired OC cell survival. In addition, overexpression of PCSK9 induced robust AKT phosphorylation along with increased expression of ERK1/2 and MEK1/2, suggesting a pro-survival role of PCSK9 in OC cells. Moreover, our drug testing revealed marked differences in cytotoxic responses to drugs targeting metabolic pathways of high-grade serous ovarian cancer (HGSOC) and low-grade serous ovarian cancer (LGSOC) PDCs. Our results show that targeting PCSK9 expression could impair OC cell survival, which warrants further investigation to address the dependency of this cancer on lipogenesis and omental metastasis. Moreover, the differences in metabolic gene expression and drug responses of OC PDCs indicate the existence of a metabolic heterogeneity within OC subtypes, which should be further explored for therapeutic improvements.

scholarly journals DNA Damage Response in Multiple Myeloma: The Role of the Tumor Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 504
Author(s):  
Takayuki Saitoh ◽  
Tsukasa Oda
Keyword(s):  
Multiple Myeloma ◽  
Dna Damage ◽  
Dna Repair ◽  
Tumor Microenvironment ◽  
Dna Damage Response ◽  
Genetic Instability ◽  
Dna Repair Mechanisms ◽  
Damage Response ◽  
Repair Mechanisms

Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by genomic instability. MM cells present various forms of genetic instability, including chromosomal instability, microsatellite instability, and base-pair alterations, as well as changes in chromosome number. The tumor microenvironment and an abnormal DNA repair function affect genetic instability in this disease. In addition, states of the tumor microenvironment itself, such as inflammation and hypoxia, influence the DNA damage response, which includes DNA repair mechanisms, cell cycle checkpoints, and apoptotic pathways. Unrepaired DNA damage in tumor cells has been shown to exacerbate genomic instability and aberrant features that enable MM progression and drug resistance. This review provides an overview of the DNA repair pathways, with a special focus on their function in MM, and discusses the role of the tumor microenvironment in governing DNA repair mechanisms.

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