In reply to Schäfer <i>et al</i>: new evidence on the role of endothelin‐1 axis as a potential therapeutic target in multiple myeloma

Russignan, Anna; Spina, Cecilia; Tamassia, Nicola; Cassaro, Adriana; Rigo, Antonella; Bagnato, Anna; Rosanò, Laura; Bonalumi, Angela; Gottardi, Michele; Zanatta, Lucia; Giacomazzi, Alice; Scupoli, Maria Teresa; Tinelli, Martina; Salvadori, Ugo; Mosna, Federico; Zamò, Alberto; Cassatella, Marco A.; Vinante, Fabrizio; Tecchio, Cristina

doi:10.1111/bjh.15240

Cited by 5 publications

(9 citation statements)

References 6 publications

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“…Of translational relevance, we demonstrate that in xenograft mouse models macitentan impairs MM cell growth and decreases MM-related vascularity. In our opinion, these data reinforce and extend the role of ET-1 axis as therapeutic target in MM ( 8 , 9 , 30 ).…”

Section: Discussionsupporting

confidence: 85%

“…In this regard, our preliminary in vitro findings indicated that macitentan can be administered in combination with other drugs already used for MM treatment. Accordingly, we found that macitentan exerts a synergistic action towards MM cells with the proteasome inhibitor bortezomib ( 9 ) and with the oral immunomodulatory imide drug pomalidomide (R.A. and C.T. unpublished results).…”

Section: Discussionmentioning

confidence: 92%

“…Preliminary results had shown that macitentan exerts significant anti-survival and anti-proliferative activities towards RPMI-8226, U266, and KMS-12-PE cells ( 9 ) ( Supplementary Figure 1 ), the first two cell lines expressing both ET A R and ET B R on the membrane, the third one (KMS-12-PE cells) ET A R only. To evaluate the mechanisms underlying the anti-proliferative action exerted by macitentan, we examined the MAPK/ERK signaling pathway, which is known to be involved in ET-1-mediated autocrine and paracrine pro-tumorigenic functions ( 7 ).…”

Section: Resultsmentioning

confidence: 99%

“…The hypoxia-mimetic agent cobalt chloride (CoCl 2, Sigma-Aldrich, Milan, Italy) was used at a concentration of 100 µM. Macitentan was purchased from Selleckchem, Munich, Germany and used at a concentration of 10 µM based on previous titration experiments ( 9 ). MM cells were treated for 24 and 48 h with 20 µmol/L of antisense oligonucleotide EZN-2968 (anti-HIF-1α) or its negative control/scrambled EZN-3088 ( 19 , 20 ) (Enzon Pharmaceuticals Inc. Piscataway, New Jersey).…”

Section: Methodsmentioning

confidence: 99%

“…Importantly, in vitro experiments consisting in ET A R or ET B R blockade with selective antagonists or with the dual receptor antagonist bosentan ( 5 ) resulted in a significantly decreased viability of MM cell lines ( 8 ). More recently, preliminary in vitro results have demonstrated that the dual receptor antagonist macitentan also decreases MM cell viability ( 9 ). Interestingly, both bosentan and macitentan are orally active drugs already licensed in clinics for the treatment of pulmonary arterial hypertension (PAH) ( 10 ).…”

Section: Introductionmentioning

confidence: 99%

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Targeting the Endothelin-1 Receptors Curtails Tumor Growth and Angiogenesis in Multiple Myeloma

et al. 2021

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The endothelin-1 (ET-1) receptors were recently found to mediate pro-survival functions in multiple myeloma (MM) cells in response to autocrine ET-1. This study investigated the effectiveness of macitentan, a dual ET-1 receptor antagonist, in MM treatment, and the mechanisms underlying its activities. Macitentan affected significantly MM cell (RPMI-8226, U266, KMS-12-PE) survival and pro-angiogenic cytokine release by down-modulating ET-1-activated MAPK/ERK and HIF-1α pathways, respectively. HIF-1α silencing abrogated the ET-1 mediated induction of genes encoding for pro-angiogenic cytokines such as VEGF-A, IL-8, Adrenomedullin, and ET-1 itself. Upon exposure to macitentan, MM cells cultured in the presence of the hypoxia-mimetic agent CoCl2, exogenous ET-1, or CoCl2 plus ET-1, down-regulated HIF-1α and the transcription and release of downstream pro-angiogenic cytokines. Consistently, macitentan limited significantly the basal pro-angiogenic activity of RPMI-8226 cells in chorioallantoic membrane assay. In xenograft mouse models, established by injecting NOG mice either via intra-caudal vein with U266 or subcutaneously with RPMI-8226 cells, macitentan reduced effectively the number of MM cells infiltrating bone marrow, and the size and microvascular density of subcutaneous MM tumors. ET-1 receptors targeting by macitentan represents an effective anti-proliferative and anti-angiogenic therapeutic approach in preclinical settings of MM.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting the Endothelin-1 Receptors Curtails Tumor Growth and Angiogenesis in Multiple Myeloma

et al. 2021

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β-arrestin1/YAP/mutant p53 complexes orchestrate the endothelin A receptor signaling in high-grade serous ovarian cancer

et al. 2019

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The limited clinical response observed in high-grade serous ovarian cancer (HG-SOC) with high frequency of TP53 mutations (mutp53) might be related to mutp53-driven oncogenic pathway network. Here we show that β-arrestin1 (β-arr1), interacts with YAP, triggering its cytoplasmic-nuclear shuttling. This interaction allows β-arr1 to recruit mutp53 to the YAP-TEAD transcriptional complex upon activation of endothelin-1 receptors (ET-1R) in patient-derived HG-SOC cells and in cell lines bearing mutp53. In parallel, β-arr1 mediates the ET-1R-induced Trio/RhoA-dependent YAP nuclear accumulation. In the nucleus, ET-1 through β-arr1 orchestrates the tethering of YAP and mutp53 to YAP/mutp53 target gene promoters, including EDN1 that ensures persistent signals. Treatment of patient-derived xenografts reveals synergistic antitumoral and antimetastatic effects of the dual ET-1R antagonist macitentan in combination with cisplatinum, shutting-down the β-arr1-mediated YAP/mutp53 transcriptional programme. Furthermore, ET A R/β-arr1/YAP gene signature correlates with a worst prognosis in HG-SOC. These findings support effective combinatorial treatment for repurposing the ET-1R antagonists in HG-SOC.

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Integrative Analysis of Proteomics and Transcriptomics Reveals Endothelin Receptor B as Novel Single Target and Identifies New Combinatorial Targets for Multiple Myeloma

Lejeune,

Köse,

Jassin

et al. 2023

HemaSphere

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Despite the recent introduction of next-generation immunotherapeutic agents, multiple myeloma (MM) remains incurable. New strategies targeting MM-specific antigens may result in a more effective therapy by preventing antigen escape, clonal evolution, and tumor resistance. In this work, we adapted an algorithm that integrates proteomic and transcriptomic results of myeloma cells to identify new antigens and possible antigen combinations. We performed cell surface proteomics on 6 myeloma cell lines based and combined these results with gene expression studies. Our algorithm identified 209 overexpressed surface proteins from which 23 proteins could be selected for combinatorial pairing. Flow cytometry analysis of 20 primary samples confirmed the expression of FCRL5, BCMA, and ICAM2 in all samples and IL6R, endothelin receptor B (ET B ), and SLCO5A1 in >60% of myeloma cases. Analyzing possible combinations, we found 6 combinatorial pairs that can target myeloma cells and avoid toxicity on other organs. In addition, our studies identified ET B as a tumor-associated antigen that is overexpressed on myeloma cells. This antigen can be targeted with a new monoclonal antibody RB49 that recognizes an epitope located in a region that becomes highly accessible after activation of ET B by its ligand. In conclusion, our algorithm identified several candidate antigens that can be used for either single-antigen targeting approaches or for combinatorial targeting in new immunotherapeutic approaches in MM.

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In reply to Schäfer et al: new evidence on the role of endothelin‐1 axis as a potential therapeutic target in multiple myeloma

Cited by 5 publications

References 6 publications

Targeting the Endothelin-1 Receptors Curtails Tumor Growth and Angiogenesis in Multiple Myeloma

Targeting the Endothelin-1 Receptors Curtails Tumor Growth and Angiogenesis in Multiple Myeloma

β-arrestin1/YAP/mutant p53 complexes orchestrate the endothelin A receptor signaling in high-grade serous ovarian cancer

Integrative Analysis of Proteomics and Transcriptomics Reveals Endothelin Receptor B as Novel Single Target and Identifies New Combinatorial Targets for Multiple Myeloma

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