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Bajpai J, Saxena M, Pradhan A, Kant S. Sotatercept: A novel therapeutic approach for pulmonary arterial hypertension through transforming growth factor-β signaling modulation. World J Methodol 2025; 15:102688. [DOI: 10.5662/wjm.v15.i3.102688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 12/31/2024] [Accepted: 01/11/2025] [Indexed: 03/06/2025] Open
Abstract
Pulmonary arterial hypertension (PAH) is a progressive disease marked by degeneration of the lung’s blood vessels. As the disease progresses, the resistance to blood flow in the pulmonary arteries increases, putting a strain on the right side of the heart as it pumps blood through the lungs. PAH is characterized by changes in the structure of blood vessels and excessive cell growth. Untreated PAH leads to irreversible right-sided heart failure, often despite medical intervention. Patients experience a gradual decline in function until they are unable to perform daily activities. Advances in treatment have improved the prognosis for many PAH patients. Currently approved therapies target the prostacyclin, endothelin, nitric oxide, or phosphodiesterase pathways to slow the progression of the disease. To address the unmet need for effective PAH therapies, research efforts are focused on identifying new targets and developing therapies that specifically address the underlying disease mechanisms and restore vascular wall homeostasis. Among these, sotatercept, a fusion protein that targets the transforming growth factor-β superfamily signaling pathway, has emerged as a promising therapeutic option. In this review, we examine the available evidence from clinical trials to assess the potential of sotatercept as a treatment for PAH.
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Affiliation(s)
- Jyoti Bajpai
- Department of Respiratory Medicine, King George’s Medical University, Lucknow 226003, Uttar Pradesh, India
| | - Mehul Saxena
- Gandhi Memorial Hospital, King George’s Medical University, Lucknow 226003, Uttar Pradesh, India
| | - Akshyaya Pradhan
- Department of Cardiology, King George’s Medical University, Lucknow 226003, Uttar Pradesh, India
| | - Surya Kant
- Department of Respiratory Medicine, King George’s Medical University, Lucknow 226003, Uttar Pradesh, India
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Gangat N, Tefferi A. Emerging Pathogenetic Mechanisms and New Drugs for Anemia in Myelofibrosis and Myelodysplastic Syndromes. Am J Hematol 2025; 100 Suppl 4:51-65. [PMID: 40056069 DOI: 10.1002/ajh.27659] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 01/20/2025] [Accepted: 02/27/2025] [Indexed: 05/13/2025]
Abstract
Anemia in myeloid neoplasms is multifaceted, with heterogeneous pathogenetic mechanisms that include ineffective erythropoiesis, hepcidin-induced iron-restricted erythropoiesis, and abnormal inflammatory cytokine production. Current management of anemia is challenged by limited approved drugs that specifically treat anemia in myelofibrosis (MF) and myelodysplastic syndrome (MDS). Newer therapies target the transforming growth factor beta (TGF-β)-bone morphogenic protein/sons of mothers against decapentaplegic (BMP-SMAD) signaling pathway, which plays a significant role in ineffective erythropoiesis (SMAD 2/3) and abnormal hepcidin production (SMAD 1/5/8). These include TGF-β ligand traps (luspatercept, elritercept), activin A receptor type 1 (ACVR1)/activin receptor-like kinase 2 (ALK2) inhibitors (momelotinib, zilurgisertib), and anti-hemojuvelin antibody-based therapies (DISC-0974). Luspatercept and momelotinib are approved for anemia related to lower-risk MDS and MF, respectively, and represent an important addition to the treatment armamentarium, along with imetelstat, a telomerase inhibitor, recently ratified for anemia in lower-risk MDS. A promising strategy to overcome the limitations of existing anemia-directed therapies includes the use of drug combinations with complementary mechanisms (luspatercept + erythropoiesis stimulating agents, luspatercept + momelotinib, DISC-0974 + momelotinib), and harnessing the erythropoietic potential of sodium-glucose co-transporter-2 inhibitors (SGLT-2I). Future research should address the complex pathophysiology of anemia, standardize definitions for anemia with gender-specified cutoffs, implement uniform erythroid response criteria, and consider early therapeutic intervention in clinical trials for anemia-directed therapies.
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Affiliation(s)
- Naseema Gangat
- Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
| | - Ayalew Tefferi
- Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
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3
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Madonna R, Ghelardoni S. Sotatercept: A Crosstalk Between Pathways and Activities in the Pulmonary Circulation and Blood. Int J Mol Sci 2025; 26:4851. [PMID: 40429991 DOI: 10.3390/ijms26104851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2025] [Revised: 05/08/2025] [Accepted: 05/15/2025] [Indexed: 05/29/2025] Open
Abstract
Sotatercept selectively binds free activins and growth differentiation factors by reproducing the binding domain of the activin receptor type IIA (ACTRIIA). The sequester of activins blunts the downstream signaling pathway, resulting in the reactivation of the bone morphogenic protein (BMP) receptor type 2 signaling and inhibition of pathological remodeling in pulmonary circulation. The balance between proliferative and antiproliferative pathways is restored, with a favorable impact on the progression of pulmonary arterial hypertension (PAH). Sotatercept, first approved for the treatment of hematological disorders such as anemia, has recently received approval as a drug in the treatment of group 1 PAH, either in United States or Europe. In this review, we will discuss the application of sotatercept and its cross reactivity in function alone or in combination with other drugs currently used for PAH. We will try also to further discuss what is known regarding the hematological effects of sotatercept, both from preclinical and clinical studies points of view, since they are the root of the side effects seen in PAH trials, such as bleeding and increased hemoglobin.
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Affiliation(s)
- Rosalinda Madonna
- Department of Surgical, Medical and Molecular Pathology and Critical Area, Cardiology Division, University of Pisa, 56124 Pisa, Italy
| | - Sandra Ghelardoni
- Department of Surgical, Medical and Molecular Pathology and Critical Area, Laboratory of Biochemistry, University of Pisa, 56124 Pisa, Italy
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Tefferi A, Gangat N. Therapeutic Targeting of the Activin Receptor Signaling Pathway: Proof of Concept in Myeloid Neoplasms. Am J Hematol 2025; 100:755-757. [PMID: 39932030 DOI: 10.1002/ajh.27638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Accepted: 01/17/2025] [Indexed: 04/04/2025]
Affiliation(s)
- Ayalew Tefferi
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Naseema Gangat
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
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Miranda AC, Cornelio CK, Tran BAC, Fernandez J. Sotatercept: A First-In-Class Activin Signaling Inhibitor for Pulmonary Arterial Hypertension. J Pharm Technol 2025:87551225251317957. [PMID: 39995630 PMCID: PMC11847314 DOI: 10.1177/87551225251317957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/26/2025] Open
Abstract
Objective: The objective of the study is to review the characteristics, efficacy, safety, and clinical relevance of sotatercept in pulmonary arterial hypertension (PAH). Data Sources: A literature search containing search terms related to sotatercept and PAH was conducted. Embase via Elsevier, MEDLINE via Ovid, the medRxiv preprint server, Cochrane Library CENTRAL trials registry, and ClinicalTrials.gov were searched from inception through October 31, 2024. The package insert was utilized to obtain drug information and additional data. Study Selection and Data Extraction: Phase II-III clinical trials investigating sotatercept for PAH were included. Articles written in English were extracted while animal studies and phase I clinical trials were excluded. Data Synthesis: In patients with WHO Group 1, functional class II-III PAH, adding sotatercept to background therapy increased 6-minute walk distance in phase II-III trials. Pooled analysis from PULSAR (phase II) and STELLAR (phase III) showed improvements in pulmonary vascular resistance and NT-proBNP. Exploratory data from PULSAR revealed that BMPR2 genetic variant status was not associated with significant differences in treatment effects. SPECTRA (phase IIb) demonstrated improved right ventricular structure and function. Interim analysis from SOTERIA showed that treatment effects persist at 1 year. Conclusions: Sotatercept is a viable add-on therapy for patients with PAH Group 1 and functional class II-III. Additional data are needed to assess long-term outcomes among treatment-naïve patients and those with the most severe symptomatology.
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Affiliation(s)
- Aimon C. Miranda
- Department of Pharmacotherapeutics and Clinical Research, Taneja College of Pharmacy, University of South Florida Health, Tampa, FL, USA
| | - Cyrille K. Cornelio
- Department of Pharmacotherapeutics and Clinical Research, Taneja College of Pharmacy, University of South Florida Health, Tampa, FL, USA
| | - Bao Anh C. Tran
- Department of Pharmacotherapeutics and Clinical Research, Taneja College of Pharmacy, University of South Florida Health, Tampa, FL, USA
| | - Joel Fernandez
- Internal Medicine, Morsani College of Medicine, University of South Florida Health, Tampa, FL, USA
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Orhan B, Nazlıoğlu HÖ, Özkocaman V, Ersal T, Pinar İE, Yalçin C, Çubukçu S, Koca TG, Hunutlu FÇ, Yavuz Ş, Ali R, Özkalemkaş F. WITHDRAWN: Is TGF-β1 And SMAD-7 Expression At Diagnosis Predictive Of Treatment Response In Patients With Low-Risk Myelodysplastic Syndrome? Pathol Res Pract 2025:155839. [PMID: 40011161 DOI: 10.1016/j.prp.2025.155839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 08/31/2023] [Accepted: 02/10/2025] [Indexed: 02/28/2025]
Abstract
This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/policies/article-withdrawal.
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Affiliation(s)
- Bedrettin Orhan
- Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey.
| | | | - Vildan Özkocaman
- Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - Tuba Ersal
- Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - İbrahim Ethem Pinar
- Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - Cumali Yalçin
- Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - Sinem Çubukçu
- Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - Tuba Güllü Koca
- Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - Fazıl Çağrı Hunutlu
- Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - Şeyma Yavuz
- Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - Rıdvan Ali
- Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - Fahir Özkalemkaş
- Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
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Forbes LM, Bauer N, Bhadra A, Bogaard HJ, Choudhary G, Goss KN, Gräf S, Heresi GA, Hopper RK, Jose A, Kim Y, Klouda T, Lahm T, Lawrie A, Leary PJ, Leopold JA, Oliveira SD, Prisco SZ, Rafikov R, Rhodes CJ, Stewart DJ, Vanderpool RR, Yuan K, Zimmer A, Hemnes AR, de Jesus Perez VA, Wilkins MR. Precision Medicine for Pulmonary Vascular Disease: The Future Is Now (2023 Grover Conference Series). Pulm Circ 2025; 15:e70027. [PMID: 39749110 PMCID: PMC11693987 DOI: 10.1002/pul2.70027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Revised: 11/25/2024] [Accepted: 12/02/2024] [Indexed: 01/04/2025] Open
Abstract
Pulmonary vascular disease is not a single condition; rather it can accompany a variety of pathologies that impact the pulmonary vasculature. Applying precision medicine strategies to better phenotype, diagnose, monitor, and treat pulmonary vascular disease is increasingly possible with the growing accessibility of powerful clinical and research tools. Nevertheless, challenges exist in implementing these tools to optimal effect. The 2023 Grover Conference Series reviewed the research landscape to summarize the current state of the art and provide a better understanding of the application of precision medicine to managing pulmonary vascular disease. In particular, the following aspects were discussed: (1) Clinical phenotypes, (2) genetics, (3) epigenetics, (4) biomarker discovery, (5) application of precision biology to clinical trials, (6) the right ventricle (RV), and (7) integrating precision medicine to clinical care. The present review summarizes the content of these discussions and the prospects for the future.
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Affiliation(s)
- Lindsay M. Forbes
- Division of Pulmonary Sciences and Critical Care MedicineUniversity of ColoradoAuroraColoradoUSA
| | - Natalie Bauer
- Department of PharmacologyCollege of Medicine, University of South AlabamaMobileAlabamaUSA
- Department of Physiology and Cell BiologyUniversity of South AlabamaMobileAlabamaUSA
| | - Aritra Bhadra
- Department of PharmacologyCollege of Medicine, University of South AlabamaMobileAlabamaUSA
- Center for Lung BiologyCollege of Medicine, University of South AlabamaMobileAlabamaUSA
| | - Harm J. Bogaard
- Department of Pulmonary MedicineAmsterdam UMCAmsterdamNetherlands
| | - Gaurav Choudhary
- Division of CardiologyWarren Alpert Medical School of Brown UniversityProvidenceRhode IslandUSA
- Lifespan Cardiovascular InstituteRhode Island and Miriam HospitalsProvidenceRhode IslandUSA
- Department of CardiologyProvidence VA Medical CenterProvidenceRhode IslandUSA
| | - Kara N. Goss
- Department of Medicine and PediatricsUniversity of Texas Southwestern Medical CenterDallasTexasUSA
| | - Stefan Gräf
- Division of Computational Genomics and Genomic Medicine, Department of MedicineUniversity of Cambridge, Victor Phillip Dahdaleh Heart & Lung Research InstituteCambridgeUK
| | | | - Rachel K. Hopper
- Department of PediatricsStanford University School of MedicinePalo AltoCaliforniaUSA
| | - Arun Jose
- Division of Pulmonary, Critical Care, and Sleep MedicineUniversity of CincinnatiCincinnatiOhioUSA
| | - Yunhye Kim
- Division of Pulmonary MedicineBoston Children's HospitalBostonMAUSA
| | - Timothy Klouda
- Division of Pulmonary MedicineBoston Children's HospitalBostonMAUSA
| | - Tim Lahm
- Division of Pulmonary Sciences and Critical Care MedicineUniversity of ColoradoAuroraColoradoUSA
- Division of Pulmonary, Critical Care, and Sleep MedicineNational Jewish HealthDenverColoradoUSA
- Pulmonary and Critical Care SectionRocky Mountain Regional VA Medical CenterDenverColoradoUSA
| | - Allan Lawrie
- National Heart and Lung InstituteImperial College LondonLondonUK
| | - Peter J. Leary
- Departments of Medicine and EpidemiologyUniversity of WashingtonSeattleWashingtonUSA
| | - Jane A. Leopold
- Division of Cardiovascular MedicineBrigham and Women's Hospital, Harvard Medical SchoolBostonMassachusettsUSA
| | - Suellen D. Oliveira
- Department of Anesthesiology, Department of Physiology and BiophysicsUniversity of Illinois at ChicagoChicagoIllinoisUSA
| | - Sasha Z. Prisco
- Division of CardiovascularLillehei Heart Institute, University of MinnesotaMinneapolisMinnesotaUSA
| | - Ruslan Rafikov
- Department of MedicineIndiana UniversityIndianapolisIndianaUSA
| | | | - Duncan J. Stewart
- Ottawa Hospital Research InstituteFaculty of MedicineUniversity of OttawaOttawaOntarioCanada
| | | | - Ke Yuan
- Division of Pulmonary MedicineBoston Children's HospitalBostonMAUSA
| | - Alexsandra Zimmer
- Department of MedicineBrown UniversityProvidenceRhode IslandUSA
- Lifespan Cardiovascular InstituteRhode Island HospitalProvidenceRhode IslandUSA
| | - Anna R. Hemnes
- Division of Allergy, Pulmonary and Critical Care MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Vinicio A. de Jesus Perez
- Division of Pulmonary and Critical Care MedicineStanford University Medical CenterStanfordCaliforniaUSA
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8
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Rodriguez-Sevilla JJ, Colla S. Inflammation in myelodysplastic syndrome pathogenesis. Semin Hematol 2024; 61:385-396. [PMID: 39424469 DOI: 10.1053/j.seminhematol.2024.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Accepted: 09/17/2024] [Indexed: 10/21/2024]
Abstract
Inflammation is a key driver of the progression of preleukemic myeloid conditions, such as clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS), to myelodysplastic syndromes (MDS). Inflammation is a critical mediator in the complex interplay of the genetic, epigenetic, and microenvironmental factors contributing to clonal evolution. Under inflammatory conditions, somatic mutations in TET2, DNMT3A, and ASXL1, the most frequently mutated genes in CHIP and CCUS, induce a competitive advantage to hematopoietic stem and progenitor cells, which leads to their clonal expansion in the bone marrow. Chronic inflammation also drives metabolic reprogramming and immune system deregulation, further promoting the expansion of malignant clones. This review underscores the urgent need to fully elucidate the role of inflammation in MDS initiation and highlights the potential of the therapeutical targeting of inflammatory pathways as an early intervention in MDS.
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Affiliation(s)
| | - Simona Colla
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
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Madonna R, Biondi F. Sotatercept: New drug on the horizon of pulmonary hypertension. Vascul Pharmacol 2024; 157:107442. [PMID: 39571875 DOI: 10.1016/j.vph.2024.107442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 11/03/2024] [Accepted: 11/14/2024] [Indexed: 11/26/2024]
Abstract
Sotatercept (brand name WINREVAIR, developed by Merck) is an activin receptor type IIA-Fc (ActRIIA-Fc), working by sequestering free activins. Sotatercept restores the balance between the activin proliferative pathway and the bone morphogenic protein (BMP) antiproliferative pathway in the pulmonary arterial cirulation. Sotatercept recently received approval in the USA and in Europe for the treatment of adults with pulmonary arterial hypertension (PAH) Group 1, on top of background PAH therapy to increase exercise capacity, improve WHO functional class and reduce the risk of clinical worsening events. Nevertheless, several studies are ongoing to investigate the potential adverse reactions of the drug especially at the haematological level. We provide an overview of the clinical and preclinical evidence of the targeting the activing pathway through sotatercept on the treatment of PAH. We also discuss what other possibilities there are for the application of sotatercept in the setting of pulmonary hypertension other than PAH Group 1.
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Affiliation(s)
- Rosalinda Madonna
- Department of Surgical, Medical and Molecular Pathology and Critical Area, Cardiology Division, University of Pisa, Pisa, Italy.
| | - Filippo Biondi
- Department of Surgical, Medical and Molecular Pathology and Critical Area, Cardiology Division, University of Pisa, Pisa, Italy
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10
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Madonna R, Biondi F. Perspectives on Sotatercept in Pulmonary Arterial Hypertension. J Clin Med 2024; 13:6463. [PMID: 39518603 PMCID: PMC11547004 DOI: 10.3390/jcm13216463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 10/25/2024] [Accepted: 10/27/2024] [Indexed: 11/16/2024] Open
Abstract
Sotatercept acts as a type IIA-Fc activin receptor, thereby scavenging free activin from its physiological membrane receptor. Through this type of action, sotaterpect leads to a rebalancing of the proliferation and antiproliferation pathways of pulmonary smooth muscle cells in response to bone morphogenic protein (BMP). Although sotatercept has been approved as the fourth pillar of therapy for group 1 pulmonary arterial hypertension (PAH) in the United States and Europe, several studies are ongoing to broaden the application of the drug to non-Group 1 PAH. We provide an overview of the clinical and preclinical evidence of targeting the activation pathway by sotatercept in the treatment of PAH. We also discuss other potential applications of sotatercept in the context of pulmonary hypertension other than PAH group 1.
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Affiliation(s)
- Rosalinda Madonna
- Cardiology Division, Department of Surgical, Medical and Molecular Pathology and Critical Area, University of Pisa, 56124 Pisa, Italy;
- Cardiology Division, Pisa University Hospital, Via Paradisa, 2, 56124 Pisa, Italy
| | - Filippo Biondi
- Cardiology Division, Department of Surgical, Medical and Molecular Pathology and Critical Area, University of Pisa, 56124 Pisa, Italy;
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Teymouri F, Dasanu CA. Selecting appropriate therapy for lower-risk myelodysplastic syndromes: current state and future prospects. Expert Opin Pharmacother 2024; 25:1975-1977. [PMID: 39387446 DOI: 10.1080/14656566.2024.2415714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 10/02/2024] [Accepted: 10/08/2024] [Indexed: 10/15/2024]
Affiliation(s)
- Farzad Teymouri
- Department of Medicine, Eisenhower Health, Rancho Mirage, CA, USA
| | - Constantin A Dasanu
- Lucy Curci Cancer Center, Eisenhower Health, Rancho Mirage, CA, USA
- Department of Medical Oncology and Hematology, UC San Diego Health System, San Diego, CA, USA
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12
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Preston IR, Lewis D, Gomberg-Maitland M. Using Sotatercept in the Care of Patients With Pulmonary Arterial Hypertension. Chest 2024; 166:604-611. [PMID: 39004216 DOI: 10.1016/j.chest.2024.06.3801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 06/04/2024] [Accepted: 06/05/2024] [Indexed: 07/16/2024] Open
Abstract
Pulmonary arterial hypertension (PAH) is a rare disease of the pulmonary microvasculature leading to elevated precapillary pulmonary hypertension. Pulmonary vascular remodeling, a characteristic of PAH, is driven by dysfunctions in the signaling between the pulmonary smooth muscle and endothelial cells with abnormalities that affect cell proliferation and immune dysregulation. Sotatercept, an activin signaling inhibitor, has recently been approved by the US Food and Drug Administration for the treatment of PAH based on two pivotal clinical trials. Evidence-based clinical trials have provided a framework to guide clinicians treating the disease; however, they are not tailored to the individual patient. Often, recommendations from these data are unclear or too general, due to remaining gaps in knowledge. In this edition of "How I Do It," we provide a case-based discussion of common clinical decisions regarding diagnostic testing, choice of first-line agents, escalation of therapy, potential timing of sotatercept, safety awareness, practical use, potential management changes, and the future use of sotatercept in other pulmonary hypertension cohorts.
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Affiliation(s)
- Ioana R Preston
- Pulmonary Critical Care and Sleep Division, Tufts University School of Medicine, Boston, MA.
| | - Denise Lewis
- Division of Cardiology, George Washington University School of Medicine and Health Sciences, Washington, DC
| | - Mardi Gomberg-Maitland
- Division of Cardiology, George Washington University School of Medicine and Health Sciences, Washington, DC
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13
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Gangat N, Tefferi A. Targeting anemia in myeloid neoplasms. Am J Hematol 2024; 99:1663-1666. [PMID: 38837732 DOI: 10.1002/ajh.27408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 05/25/2024] [Indexed: 06/07/2024]
Abstract
Anemia-directed therapeutic approaches targeting the TGF-β-SMAD and HIF-PH pathways.
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Affiliation(s)
- Naseema Gangat
- Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
| | - Ayalew Tefferi
- Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
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14
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Rasheed A, Aslam S, Sadiq HZ, Ali S, Syed R, Panjiyar BK. New and Emerging Therapeutic Drugs for the Treatment of Pulmonary Arterial Hypertension: A Systematic Review. Cureus 2024; 16:e68117. [PMID: 39347150 PMCID: PMC11438555 DOI: 10.7759/cureus.68117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/29/2024] [Indexed: 10/01/2024] Open
Abstract
Pulmonary arterial hypertension (PAH) is a serious, progressive, and potentially fatal lung disease characterized by a gradual increase in mean pulmonary arterial pressure to over 20 mmHg at rest. The pathogenesis of PAH is multifactorial. It involves dynamic obstruction of the pulmonary vasculature through vasoconstriction, structural obstruction due to adverse vascular remodeling, and pathological obstruction caused by vascular fibrosis and stiffening, which reduces compliance. PAH often presents with vague initial symptoms and is frequently diagnosed at an advanced stage. The increased pulmonary arterial pressure leads to vascular remodeling, eventually resulting in right ventricular hypertrophy and failure. PAH is a rare condition with a median life expectancy of three years, underscoring the need for effective treatment alternatives. Several FDA-approved therapeutic options are available, including prostacyclin analogs (epoprostenol, iloprost, and treprostinil), the non-prostanoid IP receptor agonist selexipag, selective endothelin receptor antagonists (ERA) (ambrisentan, bosentan, and macitentan), phosphodiesterase 5 inhibitors (sildenafil and tadalafil), and the soluble guanylate cyclase (sGC) stimulator riociguat. Despite these advancements, current medications do not provide a permanent cure. This study presents an overview of current and emerging PAH therapies through a systematic literature review. It involved an analysis of nine studies and a review of 800 papers from reputable journals published between 2013 and June 2023. The research focused on drug effects on the six-minute walk distance (6-MWD) and associated side effects in randomized controlled trials. The review found that while udenafil, imatinib, racecadotril, sotatercept, anastrozole, riociguat, tacrolimus, and ralinepag were evaluated, imatinib was notably associated with adverse side effects. Conversely, udenafil, racecadotril, sotatercept, anastrozole, riociguat, tacrolimus, and ralinepag were found to be safe, well-tolerated, and effective in improving hemodynamic measures and 6-MWDs. This study aims to summarize the developing treatment options currently under clinical trials, highlighting the need for further trials before their application in clinical practice.
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Affiliation(s)
- Amir Rasheed
- Internal Medicine, Aziz Bhatti Shaheed Teaching Hospital, Gujrat, PAK
| | | | | | - Salamat Ali
- General Surgery, Aziz Bhatti Shaheed Teaching Hospital, Gujrat, PAK
| | - Rizwana Syed
- Internal Medicine, Apollo Institute of Medical Sciences and Research, Chittoor, Chittoor, IND
| | - Binay K Panjiyar
- Research, Ventolini's Lab, Texas Tech University Health Sciences Center, Odessa, USA
- Global Clinical Scholars Research Training, Harvard Medical School, Boston, USA
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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15
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Jung HY, Ryu JH, Kim MG, Huh KH, Lee KW, Jung HY, Kang KP, Ro H, Han S, Yang J. Association of Serum Activin Levels with Allograft Outcomes in Patients with Kidney Transplant: Results from the KNOW-KT. Am J Nephrol 2024; 55:245-254. [PMID: 38198780 DOI: 10.1159/000536198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 01/08/2024] [Indexed: 01/12/2024]
Abstract
INTRODUCTION Serum activin A has been reported to contribute to vascular calcification and kidney fibrosis in chronic kidney disease. We aimed to investigate whether higher serum activin levels were associated with poor allograft outcomes in patients with kidney transplantation (KT). METHODS A total of 860 KT patients from KNOW-KT (Korean Cohort Study for Outcome in Patients with Kidney Transplantation) were analyzed. We measured serum activin levels pre-KT and 1 year after KT. The primary outcome was the composite of a ≥50% decline in estimated glomerular filtration rate and graft failure. Multivariable cause-specific hazard model was used to analyze association of 1-year activin levels with the primary outcome. The secondary outcome was coronary artery calcification score (CACS) at 5 years after KT. RESULTS During the median follow-up of 6.7 years, the primary outcome occurred in 109 (12.7%) patients. The serum activin levels at 1 year were significantly lower than those at pre-KT (488.2 ± 247.3 vs. 704.0 ± 349.6). When patients were grouped based on the median activin level at 1 year, the high-activin group had a 1.91-fold higher risk (95% CI, 1.25-2.91) for the primary outcome compared to the low-activin group. A one-standard deviation increase in activin levels as a continuous variable was associated with a 1.36-fold higher risk (95% CI, 1.16-1.60) for the primary outcome. Moreover, high activin levels were significantly associated with 1.56-fold higher CACS (95% CI, 1.12-2.18). CONCLUSION Post-transplant activin levels were independently associated with allograft functions as well as coronary artery calcification in KT patients.
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Affiliation(s)
- Hui-Yun Jung
- Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, Republic of Korea
| | - Jung-Hwa Ryu
- Department of Internal Medicine, Ewha Womans University Medical Center, Seoul, Republic of Korea
| | - Myung-Gyu Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Kyu Ha Huh
- Department of Transplantation Surgery, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Kyo Won Lee
- Department of Surgery, Sungkyunkwan University, Seoul Samsung Medical Center, Seoul, Republic of Korea
| | - Hee-Yeon Jung
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Kyung Pyo Kang
- Department of Internal Medicine, Jeonbuk National University Medical School, Jeonju, Republic of Korea
| | - Han Ro
- Department of Internal Medicine, Gachon University, Gil Hospital, Incheon, Republic of Korea
| | - Seungyeup Han
- Department of Internal Medicine, Keimyung University, Dongsan Medical Center, Daegu, Republic of Korea
| | - Jaeseok Yang
- Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, Republic of Korea
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Torbic H, Tonelli AR. Sotatercept for Pulmonary Arterial Hypertension in the Inpatient Setting. J Cardiovasc Pharmacol Ther 2024; 29:10742484231225310. [PMID: 38361351 DOI: 10.1177/10742484231225310] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/17/2024]
Abstract
Patients with pulmonary arterial hypertension (PAH) who are admitted to the hospital pose a challenge to the multidisciplinary healthcare team due to the complexity of the pathophysiology of their disease state and PAH-specific medication considerations. Pulmonary arterial hypertension is a progressive disease that may lead to death as a result of right ventricular (RV) failure. During acute on chronic RV failure it is critical to decrease the pulmonary vascular resistance with the goal of improving RV function and prognosis; therefore, aggressive PAH-treatment based on disease risk stratification is essential. Pulmonary arterial hypertension treatment for acute on chronic RV failure can be impacted by end-organ damage, hemodynamic instability, drug interactions, and PAH medications dosage and delivery. Sotatercept, a first in class activin signaling inhibitor that works on the bone morphogenetic protein/activin pathway is on track for Food and Drug Administration approval for the treatment of PAH based on results of recent trials in where the medication led to clinical and hemodynamic improvements, even when added to traditional PAH-specific therapies. The purpose of this review is to highlight important considerations when starting or continuing sotatercept in patients admitted to the hospital with PAH.
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Affiliation(s)
- Heather Torbic
- Department of Pharmacy, Cleveland Clinic, Cleveland, OH, USA
| | - Adriano R Tonelli
- Department of Pulmonary, Allergy and Critical Care Medicine, Cleveland Clinic, Cleveland, OH, USA
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17
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Lan Z, Lv Z, Zuo W, Xiao Y. From bench to bedside: The promise of sotatercept in hematologic disorders. Biomed Pharmacother 2023; 165:115239. [PMID: 37516019 DOI: 10.1016/j.biopha.2023.115239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 07/24/2023] [Accepted: 07/25/2023] [Indexed: 07/31/2023] Open
Abstract
Sotatercept (ACE-011) is an activin receptor IIA-Fc (ActRIIA-Fc) fusion protein currently under investigation for its potential in the treatment of hematologic diseases. By impeding the activities of the overexpressed growth and differentiation factor 11 (GDF11), activin A, and other members of the transforming growth factor-β (TGF-β) superfamily, commonly found in hematologic disorders, sotatercept aims to restore the normal functioning of red blood cell maturation and osteoblast differentiation. This action is anticipated to enhance anemia management and hinder the progression of myeloma. Simultaneously, comprehensive research is ongoing to investigate sotatercept's pharmacokinetics and potential adverse reactions, thus laying a robust foundation for its prospective clinical use. In this review, we provide a detailed overview of TGF-β pathways in physiological and hematologic disorder contexts, outline the potential mechanism of sotatercept, and delve into its pharmacokinetics and clinical research advancements in various hematologic diseases. A particular emphasis is given to the relationship between sotatercept dosage and its efficacy or associated adverse reactions.
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Affiliation(s)
- Zehao Lan
- Department of Cardiovascular Medicine, Second Xiangya Hospital of Central South University, Changsha 410011, China; Xiangya School of Medicine, Central South University, Changsha 410013, China
| | - Zhaohua Lv
- Department of Cardiovascular Medicine, Second Xiangya Hospital of Central South University, Changsha 410011, China; Xiangya School of Medicine, Central South University, Changsha 410013, China
| | - Wanyun Zuo
- Department of Hematology, Second Xiangya Hospital of Central South University, Changsha 410011, China
| | - Yichao Xiao
- Department of Cardiovascular Medicine, Second Xiangya Hospital of Central South University, Changsha 410011, China.
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18
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Rodrigues F, Coman T, Fouquet G, Côté F, Courtois G, Trovati Maciel T, Hermine O. A deep dive into future therapies for microcytic anemias and clinical considerations. Expert Rev Hematol 2023; 16:349-364. [PMID: 37092971 DOI: 10.1080/17474086.2023.2206556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 04/20/2023] [Indexed: 04/25/2023]
Abstract
INTRODUCTION Microcytic anemias (MA) have frequent or rare etiologies. New discoveries in understanding and treatment of microcytic anemias need to be reviewed. AREAS COVERED Microcytic anemias with a focus on the most frequent causes and on monogenic diseases that are relevant for understanding biocellular mechanisms of MA. All treatments except gene therapy, with a focus on recent advances. PubMed search with references selected by expert opinion. EXPERT OPINION As the genetic and cellular backgrounds of dyserythropoiesis will continue to be clarified, collaboration with bioengineering of treatments acting specifically at the protein domain level will continue to provide new therapies in hematology as well as oncology and neurology.
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Affiliation(s)
- François Rodrigues
- Université de Paris, service d'hématologie adultes, Hôpital Necker - Enfants Malades, France
- Inserm U1163, CNRS ERL8254 Imagine Institute, Paris, France
| | - Tereza Coman
- Inserm U1163, CNRS ERL8254 Imagine Institute, Paris, France
- Département d'hématologie, Institut Gustave Roussy, Villejuif, France
| | - Guillemette Fouquet
- Université de Paris, service d'hématologie adultes, Hôpital Necker - Enfants Malades, France
- Hématologie clinique, Centre Hospitalier Sud Francilien, Corbeil Essonnes, France
| | - Francine Côté
- Inserm U1163, CNRS ERL8254 Imagine Institute, Paris, France
| | | | | | - Olivier Hermine
- Université de Paris, service d'hématologie adultes, Hôpital Necker - Enfants Malades, France
- Inserm U1163, CNRS ERL8254 Imagine Institute, Paris, France
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Awada H, Gurnari C, Xie Z, Bewersdorf JP, Zeidan AM. What's Next after Hypomethylating Agents Failure in Myeloid Neoplasms? A Rational Approach. Cancers (Basel) 2023; 15:2248. [PMID: 37190176 PMCID: PMC10137017 DOI: 10.3390/cancers15082248] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 04/07/2023] [Accepted: 04/07/2023] [Indexed: 05/17/2023] Open
Abstract
Hypomethylating agents (HMA) such as azacitidine and decitabine are a mainstay in the current management of patients with myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML) as either single agents or in multidrug combinations. Resistance to HMA is not uncommon, and it can result due to several tumor cellular adaptations. Several clinical and genomic factors have been identified as predictors of HMA resistance. However, the management of MDS/AML patients after the failure of HMA remains challenging in the absence of standardized guidelines. Indeed, this is an area of active research with several potential therapeutic agents currently under development, some of which have demonstrated therapeutic potential in early clinical trials, especially in cases with particular mutational characteristics. Here, we review the latest findings and give a rational approach for such a challenging scenario.
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Affiliation(s)
- Hussein Awada
- Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Carmelo Gurnari
- Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Zhuoer Xie
- Department of Hematology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Jan Philipp Bewersdorf
- Department of Medicine, Leukemia Service, Memorial Sloan Kettering Comprehensive Cancer Center, New York, NY 10065, USA
| | - Amer M. Zeidan
- Section of Hematology, Department of Internal Medicine, Yale University and Yale Cancer Center, New Haven, CT 06511, USA
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20
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Wang C, Sallman DA. Current Therapeutic Landscape in Lower Risk Myelodysplastic Syndromes. Curr Treat Options Oncol 2023; 24:387-408. [PMID: 36966266 DOI: 10.1007/s11864-023-01062-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/19/2023] [Indexed: 03/27/2023]
Abstract
OPINION STATEMENT Lower risk myelodysplastic syndromes are typically characterized by an indolent disease course with a relatively low risk of transformation into acute myeloid leukemia. These patients are classically identified using the revised International Prognostic Scoring System and most likely its molecular version in the near future which may change the paradigm of treatment. The overall goals of care are symptomatic control to reduce transfusion requirements and improve quality of life. Symptomatic anemia is the most common indication to initiate disease-specific therapies after the optimization of supportive measures. Currently, erythropoiesis-stimulating agents remain the standard upfront therapy for anemia, and patients with del(5q) cytogenetic changes can benefit from lenalidomide monotherapy. Other therapeutic options after failure of upfront treatment include luspatercept, hypomethylating agents, and immunosuppressive therapies after taking into account of individualized disease features. Allogeneic hematopoietic stem cell transplant is the only potentially curative option and is usually reserved for medically fit patients with severe symptomatic cytopenias who failed all standard options and/or the disease is progressing toward higher risk categories. Fortunately, novel investigational therapies are rapidly emerging by targeting different biological processes contributing to MDS pathogenesis, and eligible patients should be managed in clinical trials if available.
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Affiliation(s)
- Chen Wang
- Department of Internal Medicine, University of South Florida, Morsani College of Medicine, Tampa, FL, USA
- Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA
| | - David A Sallman
- Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
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21
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Humbert M, McLaughlin V, Gibbs JSR, Gomberg-Maitland M, Hoeper MM, Preston IR, Souza R, Waxman AB, Ghofrani HA, Escribano Subias P, Feldman J, Meyer G, Montani D, Olsson KM, Manimaran S, de Oliveira Pena J, Badesch DB. Sotatercept for the treatment of pulmonary arterial hypertension: PULSAR open-label extension. Eur Respir J 2023; 61:13993003.01347-2022. [PMID: 36041750 PMCID: PMC9816418 DOI: 10.1183/13993003.01347-2022] [Citation(s) in RCA: 80] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 08/02/2022] [Indexed: 01/11/2023]
Abstract
BACKGROUND In participants with pulmonary arterial hypertension, 24 weeks of sotatercept resulted in a significantly greater reduction from baseline in pulmonary vascular resistance than placebo. This report characterises the longer-term safety and efficacy of sotatercept in the PULSAR open-label extension. We report cumulative safety, and efficacy at months 18-24, for all participants treated with sotatercept. METHODS PULSAR was a phase 2, randomised, double-blind, placebo-controlled study followed by an open-label extension, which evaluated sotatercept on top of background pulmonary arterial hypertension therapy in adults. Participants originally randomised to placebo were re-randomised 1:1 to sotatercept 0.3 or 0.7 mg·kg-1 (placebo-crossed group); those initially randomised to sotatercept continued the same sotatercept dose (continued-sotatercept group). Safety was evaluated in all participants who received ≥1 dose of sotatercept. The primary efficacy endpoint was change from baseline to months 18-24 in pulmonary vascular resistance. Secondary endpoints included 6-min walk distance and functional class. Two prespecified analyses, placebo-crossed and delayed-start, evaluated efficacy irrespective of dose. RESULTS Of 106 participants enrolled in the PULSAR study, 97 continued into the extension period. Serious treatment-emergent adverse events were reported in 32 (30.8%) participants; 10 (9.6%) reported treatment-emergent adverse events leading to study discontinuation. Three (2.9%) participants died, none considered related to study drug. The placebo-crossed group demonstrated significant improvement across primary and secondary endpoints and clinical efficacy was maintained in the continued-sotatercept group. CONCLUSION These results support the longer-term safety and durability of clinical benefit of sotatercept for pulmonary arterial hypertension.
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Affiliation(s)
- Marc Humbert
- Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Vallerie McLaughlin
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
| | - J Simon R Gibbs
- National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Mardi Gomberg-Maitland
- Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
| | - Marius M Hoeper
- Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research (DZL), Hannover, Germany
| | - Ioana R Preston
- Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center, Boston, MA, USA
| | - Rogerio Souza
- Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo, Brazil
| | - Aaron B Waxman
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | | | - Pilar Escribano Subias
- Department of Cardiology, Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid, Spain
| | | | - Gisela Meyer
- Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre, Brazil
| | - David Montani
- Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Karen M Olsson
- Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research (DZL), Hannover, Germany
| | - Solaiappan Manimaran
- Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA
| | | | - David B Badesch
- Division of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
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22
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Tie Y, Tang F, Peng D, Zhang Y, Shi H. TGF-beta signal transduction: biology, function and therapy for diseases. MOLECULAR BIOMEDICINE 2022; 3:45. [PMID: 36534225 PMCID: PMC9761655 DOI: 10.1186/s43556-022-00109-9] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Accepted: 11/15/2022] [Indexed: 12/23/2022] Open
Abstract
The transforming growth factor beta (TGF-β) is a crucial cytokine that get increasing concern in recent years to treat human diseases. This signal controls multiple cellular responses during embryonic development and tissue homeostasis through canonical and/or noncanonical signaling pathways. Dysregulated TGF-β signal plays an essential role in contributing to fibrosis via promoting the extracellular matrix deposition, and tumor progression via inducing the epithelial-to-mesenchymal transition, immunosuppression, and neovascularization at the advanced stage of cancer. Besides, the dysregulation of TGF-beta signal also involves in other human diseases including anemia, inflammatory disease, wound healing and cardiovascular disease et al. Therefore, this signal is proposed to be a promising therapeutic target in these diseases. Recently, multiple strategies targeting TGF-β signals including neutralizing antibodies, ligand traps, small-molecule receptor kinase inhibitors targeting ligand-receptor signaling pathways, antisense oligonucleotides to disrupt the production of TGF-β at the transcriptional level, and vaccine are under evaluation of safety and efficacy for the forementioned diseases in clinical trials. Here, in this review, we firstly summarized the biology and function of TGF-β in physiological and pathological conditions, elaborated TGF-β associated signal transduction. And then, we analyzed the current advances in preclinical studies and clinical strategies targeting TGF-β signal transduction to treat diseases.
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Affiliation(s)
- Yan Tie
- grid.13291.380000 0001 0807 1581Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No.37 Guo Xue Xiang, Chengdu, 610041 China
| | - Fan Tang
- grid.13291.380000 0001 0807 1581Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No.37 Guo Xue Xiang, Chengdu, 610041 China ,grid.13291.380000 0001 0807 1581Orthopaedic Research Institute, Department of Orthopaedics, West China Hospital, Sichuan University, Chengdu, China
| | - Dandan Peng
- grid.13291.380000 0001 0807 1581Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No.37 Guo Xue Xiang, Chengdu, 610041 China
| | - Ye Zhang
- grid.506261.60000 0001 0706 7839Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 China
| | - Huashan Shi
- grid.13291.380000 0001 0807 1581Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No.37 Guo Xue Xiang, Chengdu, 610041 China
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Devendran A, Kar S, Bailey R, Trivieri MG. The Role of Bone Morphogenetic Protein Receptor Type 2 ( BMPR2) and the Prospects of Utilizing Induced Pluripotent Stem Cells (iPSCs) in Pulmonary Arterial Hypertension Disease Modeling. Cells 2022; 11:3823. [PMID: 36497082 PMCID: PMC9741276 DOI: 10.3390/cells11233823] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 11/25/2022] [Accepted: 11/25/2022] [Indexed: 12/03/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary vascular resistance (PVR), causing right ventricular hypertrophy and ultimately death from right heart failure. Heterozygous mutations in the bone morphogenetic protein receptor type 2 (BMPR2) are linked to approximately 80% of hereditary, and 20% of idiopathic PAH cases, respectively. While patients carrying a BMPR2 gene mutation are more prone to develop PAH than non-carriers, only 20% will develop the disease, whereas the majority will remain asymptomatic. PAH is characterized by extreme vascular remodeling that causes pulmonary arterial endothelial cell (PAEC) dysfunction, impaired apoptosis, and uncontrolled proliferation of the pulmonary arterial smooth muscle cells (PASMCs). To date, progress in understanding the pathophysiology of PAH has been hampered by limited access to human tissue samples and inadequacy of animal models to accurately mimic the pathogenesis of human disease. Along with the advent of induced pluripotent stem cell (iPSC) technology, there has been an increasing interest in using this tool to develop patient-specific cellular models that precisely replicate the pathogenesis of PAH. In this review, we summarize the currently available approaches in iPSC-based PAH disease modeling and explore how this technology could be harnessed for drug discovery and to widen our understanding of the pathophysiology of PAH.
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Affiliation(s)
- Anichavezhi Devendran
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Sumanta Kar
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Rasheed Bailey
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Maria Giovanna Trivieri
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Department of Medicine, Cardiology Unit, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Senapati J, Verstovsek S, Masarova L, Pemmaraju N, Patel KP, Montalban-Bravo G, Pierce SA, Zhou L, Garcia-Manero G, Kantarjian HM, Bose P. Impact of SF3B1 mutation in myelofibrosis. Leuk Lymphoma 2022; 63:2701-2705. [PMID: 35787095 PMCID: PMC12042189 DOI: 10.1080/10428194.2022.2095629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 06/15/2022] [Accepted: 06/20/2022] [Indexed: 01/27/2023]
Affiliation(s)
- Jayastu Senapati
- Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Srdan Verstovsek
- Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Lucia Masarova
- Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Naveen Pemmaraju
- Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Keyur P Patel
- Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | | | - Sherry A Pierce
- Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Lingsha Zhou
- Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Guillermo Garcia-Manero
- Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Hagop M Kantarjian
- Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Prithviraj Bose
- Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
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Zhao J, Wang Q, Deng X, Qian J, Tian Z, Liu Y, Li M, Zeng X. The treatment strategy of connective tissue disease associated pulmonary arterial hypertension: Evolving into the future. Pharmacol Ther 2022; 239:108192. [DOI: 10.1016/j.pharmthera.2022.108192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 04/07/2022] [Accepted: 04/18/2022] [Indexed: 11/30/2022]
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Kontandreopoulou CN, Kalopisis K, Viniou NA, Diamantopoulos P. The genetics of myelodysplastic syndromes and the opportunities for tailored treatments. Front Oncol 2022; 12:989483. [PMID: 36338673 PMCID: PMC9630842 DOI: 10.3389/fonc.2022.989483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 09/14/2022] [Indexed: 11/17/2022] Open
Abstract
Genomic instability, microenvironmental aberrations, and somatic mutations contribute to the phenotype of myelodysplastic syndrome and the risk for transformation to AML. Genes involved in RNA splicing, DNA methylation, histone modification, the cohesin complex, transcription, DNA damage response pathway, signal transduction and other pathways constitute recurrent mutational targets in MDS. RNA-splicing and DNA methylation mutations seem to occur early and are reported as driver mutations in over 50% of MDS patients. The improved understanding of the molecular landscape of MDS has led to better disease and risk classification, leading to novel therapeutic opportunities. Based on these findings, novel agents are currently under preclinical and clinical development and expected to improve the clinical outcome of patients with MDS in the upcoming years. This review provides a comprehensive update of the normal gene function as well as the impact of mutations in the pathogenesis, deregulation, diagnosis, and prognosis of MDS, focuses on the most recent advances of the genetic basis of myelodysplastic syndromes and their clinical relevance, and the latest targeted therapeutic approaches including investigational and approved agents for MDS.
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Cassanello G, Pasquale R, Barcellini W, Fattizzo B. Novel Therapies for Unmet Clinical Needs in Myelodysplastic Syndromes. Cancers (Basel) 2022; 14:4941. [PMID: 36230864 PMCID: PMC9562187 DOI: 10.3390/cancers14194941] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 10/01/2022] [Accepted: 10/05/2022] [Indexed: 11/24/2022] Open
Abstract
Myelodysplastic syndromes (MDS) are a very heterogeneous disease, with extremely variable clinical features and outcomes. Current management relies on risk stratification based on IPSS and IPSS-R, which categorizes patients into low (LR-) and high-risk (HR-) MDS. Therapeutic strategies in LR-MDS patients mainly consist of erythropoiesis stimulating agents (ESAs), transfusion support, and luspatercept or lenalidomide for selected patients. Current unmet needs include the limited options available after treatment failure, and the consequent transfusion burden with several hospital admissions and poor quality of life. Therapeutic approaches in HR-MDS patients are aimed at changing the natural course of the disease and hypometylating agents (HMA) are the first choice. The only potentially curative treatment is allogeneic stem cell transplant (allo-HCT), restricted to a minority of young and fit candidates. Patients unfit for or those that relapse after the abovementioned options harbor an adverse prognosis, with limited overall survival and frequent leukemic evolution. Recent advances in genetic mutations and intracellular pathways that are relevant for MDS pathogenesis are improving disease risk stratification and highlighting therapeutic targets addressed by novel agents. Several drugs are under evaluation for LR and HR patients, which differ by their mechanism of action, reported efficacy, and phase of development. This review analyzes the current unmet clinical needs for MDS patients and provides a critical overview of the novel agents under development in this setting.
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Affiliation(s)
- Giulio Cassanello
- Department of Oncology and Oncohematology, University of Milan, 20122 Milan, Italy
- Hematology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Raffaella Pasquale
- Hematology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Wilma Barcellini
- Hematology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Bruno Fattizzo
- Department of Oncology and Oncohematology, University of Milan, 20122 Milan, Italy
- Hematology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
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Moyo TK, Mendler JH, Itzykson R, Kishtagari A, Solary E, Seegmiller AC, Gerds AT, Ayers GD, Dezern AE, Nazha A, Valent P, van de Loosdrecht AA, Onida F, Pleyer L, Cirici BX, Tibes R, Geissler K, Komrokji RS, Zhang J, Germing U, Steensma DP, Wiseman DH, Pfeilstöecker M, Elena C, Cross NCP, Kiladjian JJ, Luebbert M, Mesa RA, Montalban-Bravo G, Sanz GF, Platzbecker U, Patnaik MM, Padron E, Santini V, Fenaux P, Savona MR. The ABNL-MARRO 001 study: a phase 1-2 study of randomly allocated active myeloid target compound combinations in MDS/MPN overlap syndromes. BMC Cancer 2022; 22:1013. [PMID: 36153475 PMCID: PMC9509596 DOI: 10.1186/s12885-022-10073-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 09/09/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) comprise several rare hematologic malignancies with shared concomitant dysplastic and proliferative clinicopathologic features of bone marrow failure and propensity of acute leukemic transformation, and have significant impact on patient quality of life. The only approved disease-modifying therapies for any of the MDS/MPN are DNA methyltransferase inhibitors (DNMTi) for patients with dysplastic CMML, and still, outcomes are generally poor, making this an important area of unmet clinical need. Due to both the rarity and the heterogeneous nature of MDS/MPN, they have been challenging to study in dedicated prospective studies. Thus, refining first-line treatment strategies has been difficult, and optimal salvage treatments following DNMTi failure have also not been rigorously studied. ABNL-MARRO (A Basket study of Novel therapy for untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes) is an international cooperation that leverages the expertise of the MDS/MPN International Working Group (IWG) and provides the framework for collaborative studies to advance treatment of MDS/MPN and to explore clinical and pathologic markers of disease severity, prognosis, and treatment response. METHODS ABNL MARRO 001 (AM-001) is an open label, randomly allocated phase 1/2 study that will test novel treatment combinations in MDS/MPNs, beginning with the novel targeted agent itacitinib, a selective JAK1 inhibitor, combined with ASTX727, a fixed dose oral combination of the DNMTi decitabine and the cytidine deaminase inhibitor cedazuridine to improve decitabine bioavailability. DISCUSSION Beyond the primary objectives of the study to evaluate the safety and efficacy of novel treatment combinations in MDS/MPN, the study will (i) Establish the ABNL MARRO infrastructure for future prospective studies, (ii) Forge innovative scientific research that will improve our understanding of pathogenetic mechanisms of disease, and (iii) Inform the clinical application of diagnostic criteria, risk stratification and prognostication tools, as well as response assessments in this heterogeneous patient population. TRIAL REGISTRATION This trial was registered with ClinicalTrials.gov on August 19, 2019 (Registration No. NCT04061421).
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Affiliation(s)
- Tamara K Moyo
- Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, Nashville, TN, 777 PRB, USA
- Levine Cancer Institute, Charlotte, NC, USA
| | - Jason H Mendler
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | | | - Ashwin Kishtagari
- Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, Nashville, TN, 777 PRB, USA
| | - Eric Solary
- Institut Gustave Roussy, Université Paris-Saclay, Villejuif, France
| | - Adam C Seegmiller
- Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, Nashville, TN, 777 PRB, USA
| | | | - Gregory D Ayers
- Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, Nashville, TN, 777 PRB, USA
| | | | | | - Peter Valent
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
| | | | - Francesco Onida
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Lisa Pleyer
- Third Medical Department With Hematology, Medical Oncology, Rheumatology and Infectiology, Paracelsus Medical University, Salzburg, Austria
- Salzburg Cancer Research Institute Center for Clinical Cancer and Immunology Trials, Salzburg, Austria
| | - Blanca Xicoy Cirici
- Institut Català d'Oncologia-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute, Universitat Autònoma de Barcelona, Bellaterr, Spain
| | | | | | | | - Jing Zhang
- University of Wisconsin-Madison, Madison, WI, USA
| | - Ulrich Germing
- Department of Hematology, Oncology, and Clinical Immunology, University of Duesseldorf, Duesseldorf, Germany
| | | | | | - Michael Pfeilstöecker
- Hanusch Hospital and Ludwig Boltzmann Institute for Hematology and Oncology, Vienna, Austria
| | | | | | - Jean-Jacques Kiladjian
- Université de Paris, APHP, Hôpital Saint-Louis, Centre d'Investigations Cliniques, INSERM CIC 1427, Paris, France
| | | | - Ruben A Mesa
- Mays Cancer Center at UT Health San Antonio MD Anderson, San Antonio, TX, USA
| | | | | | | | | | - Eric Padron
- H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | | | | | - Michael R Savona
- Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, Nashville, TN, 777 PRB, USA.
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Peng X, Zhu X, Di T, Tang F, Guo X, Liu Y, Bai J, Li Y, Li L, Zhang L. The yin-yang of immunity: Immune dysregulation in myelodysplastic syndrome with different risk stratification. Front Immunol 2022; 13:994053. [PMID: 36211357 PMCID: PMC9537682 DOI: 10.3389/fimmu.2022.994053] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 09/07/2022] [Indexed: 11/13/2022] Open
Abstract
Myelodysplastic syndrome (MDS) is a heterogeneous group of myeloid clonal diseases with diverse clinical courses, and immune dysregulation plays an important role in the pathogenesis of MDS. However, immune dysregulation is complex and heterogeneous in the development of MDS. Lower-risk MDS (LR-MDS) is mainly characterized by immune hyperfunction and increased apoptosis, and the immunosuppressive therapy shows a good response. Instead, higher-risk MDS (HR-MDS) is characterized by immune suppression and immune escape, and the immune activation therapy may improve the survival of HR-MDS. Furthermore, the immune dysregulation of some MDS changes dynamically which is characterized by the coexistence and mutual transformation of immune hyperfunction and immune suppression. Taken together, the authors think that the immune dysregulation in MDS with different risk stratification can be summarized by an advanced philosophical thought “Yin-Yang theory” in ancient China, meaning that the opposing forces may actually be interdependent and interconvertible. Clarifying the mechanism of immune dysregulation in MDS with different risk stratification can provide the new basis for diagnosis and clinical treatment. This review focuses on the manifestations and roles of immune dysregulation in the different risk MDS, and summarizes the latest progress of immunotherapy in MDS.
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Affiliation(s)
- Xiaohuan Peng
- Department of Hematology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
- Key Laboratory of the Hematology of Gansu Province, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
| | - Xiaofeng Zhu
- Department of Hematology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
- Key Laboratory of the Hematology of Gansu Province, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
| | - Tianning Di
- Department of Hematology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
- Key Laboratory of the Hematology of Gansu Province, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
| | - Futian Tang
- Key Laboratory of the Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
| | - Xiaojia Guo
- Department of Hematology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
| | - Yang Liu
- Department of Hematology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
| | - Jun Bai
- Key Laboratory of the Hematology of Gansu Province, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
| | - Yanhong Li
- Key Laboratory of the Hematology of Gansu Province, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
| | - Lijuan Li
- Department of Hematology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
- Key Laboratory of the Hematology of Gansu Province, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
- *Correspondence: Lijuan Li, ; Liansheng Zhang,
| | - Liansheng Zhang
- Department of Hematology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
- Key Laboratory of the Hematology of Gansu Province, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
- *Correspondence: Lijuan Li, ; Liansheng Zhang,
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Paracatu LC, Monlish DA, Greenberg ZJ, Fisher DAC, Walter MJ, Oh ST, Schuettpelz LG. Toll-like receptor and cytokine expression throughout the bone marrow differs between patients with low- and high-risk myelodysplastic syndromes. Exp Hematol 2022; 110:47-59. [PMID: 35367529 PMCID: PMC9590644 DOI: 10.1016/j.exphem.2022.03.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 03/14/2022] [Accepted: 03/20/2022] [Indexed: 11/20/2022]
Abstract
Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders, the pathogenesis of which involves enhanced immune signaling that promotes or selects for mutant hematopoietic stem and progenitor cells (HSPCs). In particular, toll-like receptor (TLR) expression and signaling are enhanced in MDS, and their inhibition is an attractive therapeutic strategy. Although prior studies have reported increased expression of TLR2 and its binding partners TLR1 and TLR6 in the CD34+ cells of patients with MDS (especially those with low-risk disease), TLR expression in other cell types throughout the bone marrow is largely unknown. To address this, we used mass cytometry to assess the expression of TLR1, TLR2, and TLR6 and cytokines in the bone marrow hematopoietic cells of six low/intermediate-risk and six high-risk unmatched MDS bone marrow samples, as well as healthy controls, both at baseline and in response to TLR agonists. We observed several consistent differences between the groups. Most notably, TLR expression was upregulated in multiple cell populations in the low/intermediate-risk, but not high-risk, patients. In addition, many cytokines, including interleukin-6, interleukin-8, tumor necrosis factor α, transforming growth factor β, macrophage inflammatory protein 1β, and granzyme B, were highly expressed from various cell types in low/intermediate-risk patients. However, these same cytokines, with the exception of transforming growth factor β, were expressed at lower levels in high-risk MDS. Together, these findings highlight the differential role of inflammation, and specifically TLR expression, in low/intermediate- versus high-risk MDS, and suggest that elevated TLR expression and cytokine production in multiple cell types likely influences the pathogenesis of MDS in lower-risk patients.
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Affiliation(s)
- Luana Chiquetto Paracatu
- Department of Pediatrics, Division of Hematology/Oncology, Washington University School of Medicine, St. Louis, MO
| | - Darlene A Monlish
- Department of Pediatrics, Division of Hematology/Oncology, Washington University School of Medicine, St. Louis, MO
| | - Zev J Greenberg
- Department of Pediatrics, Division of Hematology/Oncology, Washington University School of Medicine, St. Louis, MO
| | - Daniel A C Fisher
- Department of Medicine, Division of Hematology, Washington University School of Medicine, St. Louis, MO
| | - Matthew J Walter
- Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO
| | - Stephen T Oh
- Department of Medicine, Division of Hematology, Washington University School of Medicine, St. Louis, MO
| | - Laura G Schuettpelz
- Department of Pediatrics, Division of Hematology/Oncology, Washington University School of Medicine, St. Louis, MO.
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Bazinet A, Bravo GM. New Approaches to Myelodysplastic Syndrome Treatment. Curr Treat Options Oncol 2022; 23:668-687. [PMID: 35320468 DOI: 10.1007/s11864-022-00965-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/13/2022] [Indexed: 12/19/2022]
Abstract
OPINION STATEMENT The treatment of myelodysplastic syndromes (MDS) begins with risk stratification using a validated tool such as the International Prognostic Scoring System (IPSS) or its revised version (IPSS-R). This divides patients into lower- and higher- risk categories. Although treatment objectives in lower-risk MDS (LR-MDS) have traditionally been directed at improving cytopenias (usually anemia) as well as quality of life, recent data supports a potential role for early intervention in delaying transfusion dependency. In addition, careful individualized risk stratification incorporating clinical, cytogenetic, and mutational data might help identify patients at higher-than-expected risk for progression. Given the need for supportive care with red blood cell (RBC) transfusions leading to iron overload, iron chelation should be considered for patients with heavy transfusion requirements at risk for end-organ complications. For patients with LR-MDS and isolated anemia, no high-risk features, and endogenous erythropoietin (EPO) levels below 500 U/L, erythropoiesis-stimulating agents (ESAs) can be attempted to improve anemia. Some LR-MDS patient subgroups may also benefit from specific therapies including luspatercept (MDS with ring sideroblasts), lenalidomide (MDS with deletion 5q), or immunosuppressive therapy (hypocellular MDS). LR-MDS patients failing the above options, or those with multiple cytopenias and/or higher-risk features, can be considered for oral low-dose hypomethylating agent (HMA) therapy. Alternatively, these patients may be enrolled on a clinical trial with promising agents targeting the transforming-growth factor beta (TGF-β) pathway, the hypoxia-inducible factor (HIF) pathway, telomerase activity, inflammatory signaling, or the splicing machinery. In higher-risk MDS (HR-MDS), therapy seeks to modify the natural history of the disease and prolong survival. Eligible patients should be considered for curative allogeneic hematopoietic stem cell transplantation (aHSCT). Despite promising novel combinations, the HMAs azacitidine (AZA) or decitabine (DAC) are still the standard of care for these patients, with intensive chemotherapy-based approaches being a potential option in a small subset of patients. Individuals who fail to respond or progress after HMA experience dismal outcomes and represent a major unmet clinical need. Such patients should be treated as part of a clinical trial if possible. Experimental agents to consider include venetoclax, myeloid cell leukemia 1 (MCL-1) inhibitors, eprenetapopt, CPX-351, immunotherapies (directed towards CD47, TIM3, or CD70), interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors, pevonedistat, seclidemstat, and eltanexor. In this review, we extensively discuss the current landscape of experimental therapies for both LR- and HR-MDS.
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Affiliation(s)
- Alexandre Bazinet
- Department of Leukemia, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Box 428, Houston, TX, 77030, USA
| | - Guillermo Montalban Bravo
- Department of Leukemia, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Box 428, Houston, TX, 77030, USA.
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Andre P, Joshi SR, Briscoe SD, Alexander MJ, Li G, Kumar R. Therapeutic Approaches for Treating Pulmonary Arterial Hypertension by Correcting Imbalanced TGF-β Superfamily Signaling. Front Med (Lausanne) 2022; 8:814222. [PMID: 35141256 PMCID: PMC8818880 DOI: 10.3389/fmed.2021.814222] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 12/15/2021] [Indexed: 12/19/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is a rare disease characterized by high blood pressure in the pulmonary circulation driven by pathological remodeling of distal pulmonary arteries, leading typically to death by right ventricular failure. Available treatments improve physical activity and slow disease progression, but they act primarily as vasodilators and have limited effects on the biological cause of the disease—the uncontrolled proliferation of vascular endothelial and smooth muscle cells. Imbalanced signaling by the transforming growth factor-β (TGF-β) superfamily contributes extensively to dysregulated vascular cell proliferation in PAH, with overactive pro-proliferative SMAD2/3 signaling occurring alongside deficient anti-proliferative SMAD1/5/8 signaling. We review the TGF-β superfamily mechanisms underlying PAH pathogenesis, superfamily interactions with inflammation and mechanobiological forces, and therapeutic strategies under development that aim to restore SMAD signaling balance in the diseased pulmonary arterial vessels. These strategies could potentially reverse pulmonary arterial remodeling in PAH by targeting causative mechanisms and therefore hold significant promise for the PAH patient population.
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Abstract
Chronic myelomonocytic leukemia (CMML) is a rare and challenging type of myeloproliferative neoplasm. Poor prognosis and high mortality, associated predominantly with progression to secondary acute myeloid leukemia (sAML), is still an unsolved problem. Despite a growing body of knowledge about the molecular repertoire of this disease, at present, the prognostic significance of CMML-associated mutations is controversial. The absence of available CMML cell lines and the small number of patients with CMML make pre-clinical testing and clinical trials complicated. Currently, specific therapy for CMML has not been approved; most of the currently available therapeutic approaches are based on myelodysplastic syndrome (MDS) and other myeloproliferative neoplasm (MNP) studies. In this regard, the development of the robust CMML animal models is currently the focus of interest. This review describes important studies concerning animal models of CMML, examples of methodological approaches, and the obtained hematologic phenotypes.
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Renneville A, Patnaik MM, Chan O, Padron E, Solary E. Increasing recognition and emerging therapies argue for dedicated clinical trials in chronic myelomonocytic leukemia. Leukemia 2021; 35:2739-2751. [PMID: 34175902 DOI: 10.1038/s41375-021-01330-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 06/11/2021] [Accepted: 06/14/2021] [Indexed: 02/06/2023]
Abstract
Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). Median overall survival of this aggressive myeloid malignancy is only 2-3 years, with a 15-30% risk of acute leukemic transformation. The paucity of clinical trials specifically designed for CMML has made therapeutic management of CMML patients challenging. As a result, treatment paradigms for CMML patients are largely borrowed from MDS and MPN. The standard of care still relies on hydroxyurea, hypomethylating agents (HMA), and allogeneic stem cell transplantation, this latter option remaining the only potentially curative therapy. To date, approved drugs for CMML treatment are HMA, including azacitidine, decitabine, and more recently the oral combination of decitabine and cedazuridine. However, HMA treatment does not meaningfully alter the natural course of this disease. New treatment approaches for improving CMML-associated cytopenias or targeting the CMML malignant clone are emerging. More than 25 therapeutic agents are currently being evaluated in phase 1 or phase 2 clinical trials for CMML and other myeloid malignancies, often in combination with a HMA backbone. Several novel agents, such as sotatercept, ruxolitinib, lenzilumab, and tagraxofusp have shown promising clinical efficacy in CMML. Current evidence supports the idea that effective treatment in CMML will likely require combination therapy targeting multiple pathways, which emphasizes the need for additional new therapeutic options. This review focuses on recent therapeutic advances and innovative treatment strategies in CMML, including global and molecularly targeted approaches. We also discuss what may help to make progress in the design of rationally derived and disease-modifying therapies for CMML.
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Affiliation(s)
| | - Mrinal M Patnaik
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Onyee Chan
- Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL, USA
| | - Eric Padron
- Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL, USA
| | - Eric Solary
- INSERM U1287, Gustave Roussy Cancer Campus, Villejuif, France. .,Faculty of Medicine, Université Paris-Sud, Le Kremlin-Bicêtre, France. .,Department of Hematology, Gustave Roussy Cancer Campus, Villejuif, France.
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Zhao G, Wang Q, Li S, Wang X. Resistance to Hypomethylating Agents in Myelodysplastic Syndrome and Acute Myeloid Leukemia From Clinical Data and Molecular Mechanism. Front Oncol 2021; 11:706030. [PMID: 34650913 PMCID: PMC8505973 DOI: 10.3389/fonc.2021.706030] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 09/08/2021] [Indexed: 11/13/2022] Open
Abstract
The nucleoside analogs decitabine (5-AZA-dC) and azacitidine (5-AZA) have been developed as targeted therapies to reverse DNA methylation in different cancer types, and they significantly improve the survival of patients who are not suitable for traditional intensive chemotherapies or other treatment regimens. However, approximately 50% of patients have a response to hypomethylating agents (HMAs), and many patients have no response originally or in the process of treatment. Even though new combination regimens have been tested to overcome the resistance to 5-AZA-dC or 5-AZA, only a small proportion of patients benefited from these strategies, and the outcome was very poor. However, the mechanisms of the resistance remain unknown. Some studies only partially described management after failure and the mechanisms of resistance. Herein, we will review the clinical and molecular signatures of the HMA response, alternative treatment after failure, and the causes of resistance in hematological malignancies.
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Affiliation(s)
| | | | | | - Xiaoqin Wang
- Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China
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36
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Andrews RE, Brown JE, Lawson MA, Chantry AD. Myeloma Bone Disease: The Osteoblast in the Spotlight. J Clin Med 2021; 10:jcm10173973. [PMID: 34501423 PMCID: PMC8432062 DOI: 10.3390/jcm10173973] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 08/24/2021] [Accepted: 08/27/2021] [Indexed: 12/17/2022] Open
Abstract
Lytic bone disease remains a life-altering complication of multiple myeloma, with up to 90% of sufferers experiencing skeletal events at some point in their cancer journey. This tumour-induced bone disease is driven by an upregulation of bone resorption (via increased osteoclast (OC) activity) and a downregulation of bone formation (via reduced osteoblast (OB) activity), leading to phenotypic osteolysis. Treatments are limited, and currently exclusively target OCs. Despite existing bone targeting therapies, patients successfully achieving remission from their cancer can still be left with chronic pain, poor mobility, and reduced quality of life as a result of bone disease. As such, the field is desperately in need of new and improved bone-modulating therapeutic agents. One such option is the use of bone anabolics, drugs that are gaining traction in the osteoporosis field following successful clinical trials. The prospect of using these therapies in relation to myeloma is an attractive option, as they aim to stimulate OBs, as opposed to existing therapeutics that do little to orchestrate new bone formation. The preclinical application of bone anabolics in myeloma mouse models has demonstrated positive outcomes for bone repair and fracture resistance. Here, we review the role of the OB in the pathophysiology of myeloma-induced bone disease and explore whether novel OB targeted therapies could improve outcomes for patients.
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Affiliation(s)
- Rebecca E. Andrews
- Department of Oncology and Metabolism, The Medical School, The University of Sheffield, Sheffield S10 2RX, UK; (J.E.B.); (M.A.L.); (A.D.C.)
- Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield S10 2JF, UK
- Correspondence:
| | - Janet E. Brown
- Department of Oncology and Metabolism, The Medical School, The University of Sheffield, Sheffield S10 2RX, UK; (J.E.B.); (M.A.L.); (A.D.C.)
- Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield S10 2JF, UK
| | - Michelle A. Lawson
- Department of Oncology and Metabolism, The Medical School, The University of Sheffield, Sheffield S10 2RX, UK; (J.E.B.); (M.A.L.); (A.D.C.)
| | - Andrew D. Chantry
- Department of Oncology and Metabolism, The Medical School, The University of Sheffield, Sheffield S10 2RX, UK; (J.E.B.); (M.A.L.); (A.D.C.)
- Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield S10 2JF, UK
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Yang Z, Yan L, Cao H, Gu Y, Zhou P, Shi M, Li G, Jiao X, Li N, Li X, Sun K, Shao F. Erythropoietin Protects against Diffuse Alveolar Hemorrhage in Mice by Regulating Macrophage Polarization through the EPOR/JAK2/STAT3 Axis. THE JOURNAL OF IMMUNOLOGY 2021; 206:1752-1764. [PMID: 33811103 DOI: 10.4049/jimmunol.1901312] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 02/08/2021] [Indexed: 11/19/2022]
Abstract
Macrophages play an important role in the pathogenesis of systemic lupus erythematosus-associated diffuse alveolar hemorrhage (DAH). The immunomodulation of macrophage responses might be a potential approach for the prevention and treatment of DAH. Erythropoietin (EPO) could regulate macrophage bioactivities by binding to the EPO receptor expressing on macrophages. This study assessed the effects of EPO on DAH protection using an immune-mediated DAH murine model with macrophages as the major contributor. A DAH murine model was established in female C57BL/6 mice by an i.p. injection of pristane. We found that EPO administration alleviates DAH by reducing pulmonary macrophages recruitment and promoting phenotype switch toward M2 macrophages in vivo. EPO drove macrophages to the anti-inflammatory phenotype in the primary murine bone marrow-derived macrophages and macrophages cell line RAW 264.7 with LPS, IFN-γ, and IL-4 in vitro. Moreover, EPO treatment increases the expression of EPOR and decreases the expression of miR-494-3p, resulting in increased phosphorylation of JAK2 and STAT3. In conclusion, EPO can be a potential therapeutic agent in DAH by reducing cell apoptosis and regulating macrophage polarization through the EPOR/JAK2/STAT3 axis. Further studies are also needed to validate the direct target of miR-494-3p in regulating JAK2/STAT3 signaling transduction.
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Affiliation(s)
- Zhongnan Yang
- Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China.,Department of Urology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China
| | - Lei Yan
- Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China
| | - Huixia Cao
- Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China
| | - Yue Gu
- Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China
| | - Pan Zhou
- Department of Hematology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China; and
| | - Mingyue Shi
- Department of Hematology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China; and
| | - Guodong Li
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Xiaojing Jiao
- Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China
| | - Na Li
- Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China
| | - Xiangnan Li
- Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China
| | - Kai Sun
- Department of Hematology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China; and
| | - Fengmin Shao
- Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, China;
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Esposito P, Verzola D, Picciotto D, Cipriani L, Viazzi F, Garibotto G. Myostatin/Activin-A Signaling in the Vessel Wall and Vascular Calcification. Cells 2021; 10:2070. [PMID: 34440838 PMCID: PMC8393536 DOI: 10.3390/cells10082070] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 08/11/2021] [Accepted: 08/11/2021] [Indexed: 02/07/2023] Open
Abstract
A current hypothesis is that transforming growth factor-β signaling ligands, such as activin-A and myostatin, play a role in vascular damage in atherosclerosis and chronic kidney disease (CKD). Myostatin and activin-A bind with different affinity the activin receptors (type I or II), activating distinct intracellular signaling pathways and finally leading to modulation of gene expression. Myostatin and activin-A are expressed by different cell types and tissues, including muscle, kidney, reproductive system, immune cells, heart, and vessels, where they exert pleiotropic effects. In arterial vessels, experimental evidence indicates that myostatin may mostly promote vascular inflammation and premature aging, while activin-A is involved in the pathogenesis of vascular calcification and CKD-related mineral bone disorders. In this review, we discuss novel insights into the biology and physiology of the role played by myostatin and activin in the vascular wall, focusing on the experimental and clinical data, which suggest the involvement of these molecules in vascular remodeling and calcification processes. Moreover, we describe the strategies that have been used to modulate the activin downward signal. Understanding the role of myostatin/activin signaling in vascular disease and bone metabolism may provide novel therapeutic opportunities to improve the treatment of conditions still associated with high morbidity and mortality.
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Affiliation(s)
- Pasquale Esposito
- Department of Internal Medicine, University of Genova, 16132 Genova, Italy; (P.E.); (D.V.); (L.C.); (F.V.)
- IRCCS Ospedale Policlinico San Martino, Clinica Nefrologica, Dialisi, Trapianto, 16132 Genova, Italy;
| | - Daniela Verzola
- Department of Internal Medicine, University of Genova, 16132 Genova, Italy; (P.E.); (D.V.); (L.C.); (F.V.)
| | - Daniela Picciotto
- IRCCS Ospedale Policlinico San Martino, Clinica Nefrologica, Dialisi, Trapianto, 16132 Genova, Italy;
| | - Leda Cipriani
- Department of Internal Medicine, University of Genova, 16132 Genova, Italy; (P.E.); (D.V.); (L.C.); (F.V.)
| | - Francesca Viazzi
- Department of Internal Medicine, University of Genova, 16132 Genova, Italy; (P.E.); (D.V.); (L.C.); (F.V.)
- IRCCS Ospedale Policlinico San Martino, Clinica Nefrologica, Dialisi, Trapianto, 16132 Genova, Italy;
| | - Giacomo Garibotto
- Department of Internal Medicine, University of Genova, 16132 Genova, Italy; (P.E.); (D.V.); (L.C.); (F.V.)
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39
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Platzbecker U, Kubasch AS, Homer-Bouthiette C, Prebet T. Current challenges and unmet medical needs in myelodysplastic syndromes. Leukemia 2021; 35:2182-2198. [PMID: 34045662 PMCID: PMC8324480 DOI: 10.1038/s41375-021-01265-7] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 04/01/2021] [Accepted: 04/26/2021] [Indexed: 01/29/2023]
Abstract
Myelodysplastic syndromes (MDS) represent a heterogeneous group of myeloid neoplasms that are characterized by ineffective hematopoiesis, variable cytopenias, and a risk of progression to acute myeloid leukemia. Most patients with MDS are affected by anemia and anemia-related symptoms, which negatively impact their quality of life. While many patients with MDS have lower-risk disease and are managed by existing treatments, there currently is no clear standard of care for many patients. For patients with higher-risk disease, the treatment priority is changing the natural history of the disease by delaying disease progression to acute myeloid leukemia and improving overall survival. However, existing treatments for MDS are generally not curative and many patients experience relapse or resistance to first-line treatment. Thus, there remains an unmet need for new, more effective but tolerable strategies to manage MDS. Recent advances in molecular diagnostics have improved our understanding of the pathogenesis of MDS, and it is becoming clear that the diverse nature of genetic abnormalities that drive MDS demands a complex and personalized treatment approach. This review will discuss some of the challenges related to the current MDS treatment landscape, as well as new approaches currently in development.
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Affiliation(s)
- Uwe Platzbecker
- Department of Hematology, Cellular Therapy and Hemostaseology, Leipzig University Hospital, Leipzig, Germany.
- German MDS Study Group (D-MDS), Leipzig, Germany.
- The European Myelodysplastic Syndromes Cooperative Group (EMSCO), Leipzig, Germany.
| | - Anne Sophie Kubasch
- Department of Hematology, Cellular Therapy and Hemostaseology, Leipzig University Hospital, Leipzig, Germany
- German MDS Study Group (D-MDS), Leipzig, Germany
- The European Myelodysplastic Syndromes Cooperative Group (EMSCO), Leipzig, Germany
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40
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Cullivan S, Murphy CA, Weiss L, Comer SP, Kevane B, McCullagh B, Maguire PB, Ní Ainle F, Gaine SP. Platelets, extracellular vesicles and coagulation in pulmonary arterial hypertension. Pulm Circ 2021; 11:20458940211021036. [PMID: 34158919 PMCID: PMC8182202 DOI: 10.1177/20458940211021036] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Accepted: 05/10/2021] [Indexed: 01/01/2023] Open
Abstract
Pulmonary arterial hypertension is a rare disease of the pulmonary vasculature, characterised pathologically by proliferation, remodelling and thrombosis in situ. Unfortunately, existing therapeutic interventions do not reverse these findings and the disease continues to result in significant morbidity and premature mortality. A number of haematological derangements have been described in pulmonary arterial hypertension which may provide insights into the pathobiology of the disease and opportunities to explore new therapeutic pathways. These include quantitative and qualitative platelet abnormalities, such as thrombocytopaenia, increased mean platelet volume and altered platelet bioenergetics. Furthermore, a hypercoagulable state and aberrant negative regulatory pathways can be observed, which could contribute to thrombosis in situ in distal pulmonary arteries and arterioles. Finally, there is increasing interest in the role of extracellular vesicle autocrine and paracrine signalling in pulmonary arterial hypertension, and their potential utility as biomarkers and novel therapeutic targets. This review focuses on the potential role of platelets, extracellular vesicles and coagulation pathways in the pathobiology of pulmonary arterial hypertension. We highlight important unanswered clinical questions and the implications of these observations for future research and pulmonary arterial hypertension-directed therapies.
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Affiliation(s)
- Sarah Cullivan
- National Pulmonary Hypertension Unit, Mater
Misericordiae University Hospital, Dublin, Ireland
- Conway-SPHERE Research Group, Conway Institute,
University College Dublin, Dublin, Ireland
| | - Claire A. Murphy
- Conway-SPHERE Research Group, Conway Institute,
University College Dublin, Dublin, Ireland
- Department of Neonatology, Rotunda Hospital, Dublin,
Ireland
| | - Luisa Weiss
- Conway-SPHERE Research Group, Conway Institute,
University College Dublin, Dublin, Ireland
| | - Shane P. Comer
- Conway-SPHERE Research Group, Conway Institute,
University College Dublin, Dublin, Ireland
| | - Barry Kevane
- Conway-SPHERE Research Group, Conway Institute,
University College Dublin, Dublin, Ireland
- Department of Haematology, Mater Misericordiae
University Hospital, Dublin, Ireland
| | - Brian McCullagh
- National Pulmonary Hypertension Unit, Mater
Misericordiae University Hospital, Dublin, Ireland
| | - Patricia B. Maguire
- Conway-SPHERE Research Group, Conway Institute,
University College Dublin, Dublin, Ireland
| | - Fionnuala Ní Ainle
- Conway-SPHERE Research Group, Conway Institute,
University College Dublin, Dublin, Ireland
- Department of Haematology, Mater Misericordiae
University Hospital, Dublin, Ireland
| | - Sean P. Gaine
- National Pulmonary Hypertension Unit, Mater
Misericordiae University Hospital, Dublin, Ireland
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41
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Yung LM, Yang P, Joshi S, Augur ZM, Kim SSJ, Bocobo GA, Dinter T, Troncone L, Chen PS, McNeil ME, Southwood M, Poli de Frias S, Knopf J, Rosas IO, Sako D, Pearsall RS, Quisel JD, Li G, Kumar R, Yu PB. ACTRIIA-Fc rebalances activin/GDF versus BMP signaling in pulmonary hypertension. Sci Transl Med 2021; 12:12/543/eaaz5660. [PMID: 32404506 DOI: 10.1126/scitranslmed.aaz5660] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 01/22/2020] [Accepted: 04/17/2020] [Indexed: 12/13/2022]
Abstract
Human genetics, biomarker, and animal studies implicate loss of function in bone morphogenetic protein (BMP) signaling and maladaptive transforming growth factor-β (TGFβ) signaling as drivers of pulmonary arterial hypertension (PAH). Although sharing common receptors and effectors with BMP/TGFβ, the function of activin and growth and differentiation factor (GDF) ligands in PAH are less well defined. Increased expression of GDF8, GDF11, and activin A was detected in lung lesions from humans with PAH and experimental rodent models of pulmonary hypertension (PH). ACTRIIA-Fc, a potent GDF8/11 and activin ligand trap, was used to test the roles of these ligands in animal and cellular models of PH. By blocking GDF8/11- and activin-mediated SMAD2/3 activation in vascular cells, ACTRIIA-Fc attenuated proliferation of pulmonary arterial smooth muscle cells and pulmonary microvascular endothelial cells. In several experimental models of PH, prophylactic administration of ACTRIIA-Fc markedly improved hemodynamics, right ventricular (RV) hypertrophy, RV function, and arteriolar remodeling. When administered after the establishment of hemodynamically severe PH in a vasculoproliferative model, ACTRIIA-Fc was more effective than vasodilator in attenuating PH and arteriolar remodeling. Potent antiremodeling effects of ACTRIIA-Fc were associated with inhibition of SMAD2/3 activation and downstream transcriptional activity, inhibition of proliferation, and enhancement of apoptosis in the vascular wall. ACTRIIA-Fc reveals an unexpectedly prominent role of GDF8, GDF11, and activin as drivers of pulmonary vascular disease and represents a therapeutic strategy for restoring the balance between SMAD1/5/9 and SMAD2/3 signaling in PAH.
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Affiliation(s)
- Lai-Ming Yung
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Peiran Yang
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | | | - Zachary M Augur
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Stephanie S J Kim
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Geoffrey A Bocobo
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Teresa Dinter
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Luca Troncone
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Po-Sheng Chen
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.,Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan City 704, Taiwan
| | - Megan E McNeil
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Mark Southwood
- Department of Pathology, Royal Papworth Hospital, Cambridge CB2 0AY, UK
| | - Sergio Poli de Frias
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - John Knopf
- Acceleron Pharma Inc., Cambridge, MA 02139, USA
| | - Ivan O Rosas
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Dianne Sako
- Acceleron Pharma Inc., Cambridge, MA 02139, USA
| | | | | | - Gang Li
- Acceleron Pharma Inc., Cambridge, MA 02139, USA
| | | | - Paul B Yu
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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Lodberg A. Principles of the activin receptor signaling pathway and its inhibition. Cytokine Growth Factor Rev 2021; 60:1-17. [PMID: 33933900 DOI: 10.1016/j.cytogfr.2021.04.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/14/2021] [Accepted: 04/15/2021] [Indexed: 01/19/2023]
Abstract
This review captures the anabolic and stimulatory effects observed with inhibition of the transforming growth factor β superfamily in muscle, blood, and bone. New medicinal substances that rectify activin, myostatin, and growth differentiation factor 11 signaling give hope to the many whose lives are affected by deterioration of these tissues. The review first covers the origin, structure, and common pathway of activins, myostatin, and growth differentiation factor 11 along with the pharmacodynamics of the new class of molecules designed to oppose the activin receptor signaling pathway. Current terminology surrounding this new class of molecules is inconsistent and does not infer functionality. Adopting inhibitors of the activin receptor signaling pathway (IASPs) as a generic term is proposed because it encapsulates the molecular mechanisms along the pathway trajectory. To conclude, a pragmatic classification of IASPs is presented that integrates functionality and side effects based on the data available from animals and humans. This provides researchers and clinicians with a tool to tailor IASPs therapy according to the need of projects or patients and with respect to side effects.
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Affiliation(s)
- Andreas Lodberg
- Department of Biomedicine, Aarhus University, Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Wilhelm Meyers Allé, DK-8000, Aarhus, Denmark.
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Humbert M, McLaughlin V, Gibbs JSR, Gomberg-Maitland M, Hoeper MM, Preston IR, Souza R, Waxman A, Escribano Subias P, Feldman J, Meyer G, Montani D, Olsson KM, Manimaran S, Barnes J, Linde PG, de Oliveira Pena J, Badesch DB. Sotatercept for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med 2021; 384:1204-1215. [PMID: 33789009 DOI: 10.1056/nejmoa2024277] [Citation(s) in RCA: 287] [Impact Index Per Article: 71.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND Pulmonary arterial hypertension is characterized by pulmonary vascular remodeling, cellular proliferation, and poor long-term outcomes. Dysfunctional bone morphogenetic protein pathway signaling is associated with both hereditary and idiopathic subtypes. Sotatercept, a novel fusion protein, binds activins and growth differentiation factors in the attempt to restore balance between growth-promoting and growth-inhibiting signaling pathways. METHODS In this 24-week multicenter trial, we randomly assigned 106 adults who were receiving background therapy for pulmonary arterial hypertension to receive subcutaneous sotatercept at a dose of 0.3 mg per kilogram of body weight every 3 weeks or 0.7 mg per kilogram every 3 weeks or placebo. The primary end point was the change from baseline to week 24 in pulmonary vascular resistance. RESULTS Baseline characteristics were similar among the three groups. The least-squares mean difference between the sotatercept 0.3-mg group and the placebo group in the change from baseline to week 24 in pulmonary vascular resistance was -145.8 dyn · sec · cm-5 (95% confidence interval [CI], -241.0 to -50.6; P = 0.003). The least-squares mean difference between the sotatercept 0.7-mg group and the placebo group was -239.5 dyn · sec · cm-5 (95% CI, -329.3 to -149.7; P<0.001). At 24 weeks, the least-squares mean difference between the sotatercept 0.3-mg group and the placebo group in the change from baseline in 6-minute walk distance was 29.4 m (95% CI, 3.8 to 55.0). The least-squares mean difference between the sotatercept 0.7-mg group and the placebo group was 21.4 m (95% CI, -2.8 to 45.7). Sotatercept was also associated with a decrease in N-terminal pro-B-type natriuretic peptide levels. Thrombocytopenia and an increased hemoglobin level were the most common hematologic adverse events. One patient in the sotatercept 0.7-mg group died from cardiac arrest. CONCLUSIONS Treatment with sotatercept resulted in a reduction in pulmonary vascular resistance in patients receiving background therapy for pulmonary arterial hypertension. (Funded by Acceleron Pharma; PULSAR ClinicalTrials.gov number, NCT03496207.).
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Affiliation(s)
- Marc Humbert
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - Vallerie McLaughlin
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - J Simon R Gibbs
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - Mardi Gomberg-Maitland
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - Marius M Hoeper
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - Ioana R Preston
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - Rogerio Souza
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - Aaron Waxman
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - Pilar Escribano Subias
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - Jeremy Feldman
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - Gisela Meyer
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - David Montani
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - Karen M Olsson
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - Solaiappan Manimaran
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - Jennifer Barnes
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - Peter G Linde
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - Janethe de Oliveira Pena
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - David B Badesch
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
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Molecular Targeted Therapy in Myelodysplastic Syndromes: New Options for Tailored Treatments. Cancers (Basel) 2021; 13:cancers13040784. [PMID: 33668555 PMCID: PMC7917605 DOI: 10.3390/cancers13040784] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/08/2021] [Accepted: 02/09/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary Myelodysplastic syndromes (MDS) are a group of diseases in which bone marrow stem cells acquire genetic alterations and can initiate leukemia, blocking the production of mature blood cells. It is of crucial importance to identify those genetic abnormalities because some of them can be the targeted. To date only very few drugs are approved for patients manifesting this group of disorders and there is an urgent need to develop new effective therapies. This review gives an overview of the genetic of MDS and the therapeutic options available and in clinical experimentation. Abstract Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis, progressive cytopenias and increased risk of transformation to acute myeloid leukemia. The improved understanding of the underlying biology and genetics of MDS has led to better disease and risk classification, paving the way for novel therapeutic opportunities. Indeed, we now have a vast pipeline of targeted agents under pre-clinical and clinical development, potentially able to modify the natural history of the diverse disease spectrum of MDS. Here, we review the latest therapeutic approaches (investigational and approved agents) for MDS treatment. A deep insight will be given to molecularly targeted therapies by reviewing new agents for individualized precision medicine.
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Chan O, Komrokji RS. Luspatercept in the treatment of lower-risk myelodysplastic syndromes. Future Oncol 2021; 17:1473-1481. [PMID: 33511859 DOI: 10.2217/fon-2020-1093] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Transforming growth factor beta (TGF-β) signaling pathway is key to hematopoiesis regulation. Increased activation of this pathway contributes to ineffective terminal erythroid differentiation in myelodysplastic syndromes (MDS). Luspatercept is a novel fusion protein that traps TGF-β ligands preventing them from binding to Type II TGF-β receptors, thereby decreasing phosphorylated SMAD2/3 resulting in the downstream effect of promoting erythropoiesis. Seminal clinical trials using luspatercept, PACE-MD and MEDALIST, demonstrated impressive efficacy in the treatment of transfusion-dependent anemia in intermediate risk or lower MDS had led to the US FDA approval for this indication. This review summarizes luspatercept mechanisms of action, efficacy/safety data supporting its use and ongoing clinical trials in MDS.
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Affiliation(s)
- Onyee Chan
- Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Rami S Komrokji
- Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL 33612, USA
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Lewis R, Bewersdorf JP, Zeidan AM. Clinical Management of Anemia in Patients with Myelodysplastic Syndromes: An Update on Emerging Therapeutic Options. Cancer Manag Res 2021; 13:645-657. [PMID: 33531837 PMCID: PMC7846829 DOI: 10.2147/cmar.s240600] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Accepted: 01/13/2021] [Indexed: 12/18/2022] Open
Abstract
For the majority of patients with lower-risk myelodysplastic syndrome (LR-MDS), one of the primary clinical goals is to alleviate the symptoms associated with the resultant cytopenias and to minimize the transfusion burden. While supportive red blood cell (RBC) transfusions and erythropoiesis-stimulating agents (ESAs) may lead to clinical improvement, frequent transfusions are often complicated by iron overload and decreased quality of life; furthermore, most patients either do not respond to ESAs or will eventually develop resistance. As such, there is a great need for further therapeutic options in the management of anemia related to MDS. Several additional therapeutics are now available in select patients with LR-MDS and symptomatic anemia including luspatercept, lenalidomide, and immunosuppressive therapy. Furthermore, several novel agents are currently in development to address this area of clinical need such as imetelstat and roxadustat. In this article, we review the currently available therapeutic options for symptomatic anemia in LR-MDS as well as review the therapeutic agents in development.
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Affiliation(s)
- Russell Lewis
- Department of Medicine, Section of Hematology, Yale University, New Haven, CT, USA
| | | | - Amer M Zeidan
- Department of Medicine, Section of Hematology, Yale University, New Haven, CT, USA
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Parisi S, Finelli C, Fazio A, De Stefano A, Mongiorgi S, Ratti S, Cappellini A, Billi AM, Cocco L, Follo MY, Manzoli L. Clinical and Molecular Insights in Erythropoiesis Regulation of Signal Transduction Pathways in Myelodysplastic Syndromes and β-Thalassemia. Int J Mol Sci 2021; 22:ijms22020827. [PMID: 33467674 PMCID: PMC7830211 DOI: 10.3390/ijms22020827] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/12/2021] [Accepted: 01/13/2021] [Indexed: 01/19/2023] Open
Abstract
Erythropoiesis regulation is essential in normal physiology and pathology, particularly in myelodysplastic syndromes (MDS) and β-thalassemia. Several signaling transduction processes, including those regulated by inositides, are implicated in erythropoiesis, and the latest MDS or β-thalassemia preclinical and clinical studies are now based on their regulation. Among others, the main pathways involved are those regulated by transforming growth factor (TGF)-β, which negatively regulates erythrocyte differentiation and maturation, and erythropoietin (EPO), which acts on the early-stage erythropoiesis. Also small mother against decapentaplegic (SMAD) signaling molecules play a role in pathology, and activin receptor ligand traps are being investigated for future clinical applications. Even inositide-dependent signaling, which is important in the regulation of cell proliferation and differentiation, is specifically associated with erythropoiesis, with phospholipase C (PLC) and phosphatidylinositol 3-kinase (PI3K) as key players that are becoming increasingly important as new promising therapeutic targets. Additionally, Roxadustat, a new erythropoiesis stimulating agent targeting hypoxia inducible factor (HIF), is under clinical development. Here, we review the role and function of the above-mentioned signaling pathways, and we describe the state of the art and new perspectives of erythropoiesis regulation in MDS and β-thalassemia.
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Affiliation(s)
- Sarah Parisi
- Department of Oncology and Hematology, IRCCS-Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (S.P.); (C.F.)
- Department of Experimental, Diagnostic and Specialty Medicine DIMES, Institute of Hematology “L. and A. Seràgnoli”, University of Bologna, 40138 Bologna, Italy
| | - Carlo Finelli
- Department of Oncology and Hematology, IRCCS-Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (S.P.); (C.F.)
- Department of Experimental, Diagnostic and Specialty Medicine DIMES, Institute of Hematology “L. and A. Seràgnoli”, University of Bologna, 40138 Bologna, Italy
| | - Antonietta Fazio
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy; (A.F.); (A.D.S.); (S.M.); (S.R.); (A.C.); (A.M.B.); (L.C.); (L.M.)
| | - Alessia De Stefano
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy; (A.F.); (A.D.S.); (S.M.); (S.R.); (A.C.); (A.M.B.); (L.C.); (L.M.)
| | - Sara Mongiorgi
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy; (A.F.); (A.D.S.); (S.M.); (S.R.); (A.C.); (A.M.B.); (L.C.); (L.M.)
| | - Stefano Ratti
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy; (A.F.); (A.D.S.); (S.M.); (S.R.); (A.C.); (A.M.B.); (L.C.); (L.M.)
| | - Alessandra Cappellini
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy; (A.F.); (A.D.S.); (S.M.); (S.R.); (A.C.); (A.M.B.); (L.C.); (L.M.)
| | - Anna Maria Billi
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy; (A.F.); (A.D.S.); (S.M.); (S.R.); (A.C.); (A.M.B.); (L.C.); (L.M.)
| | - Lucio Cocco
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy; (A.F.); (A.D.S.); (S.M.); (S.R.); (A.C.); (A.M.B.); (L.C.); (L.M.)
| | - Matilde Y. Follo
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy; (A.F.); (A.D.S.); (S.M.); (S.R.); (A.C.); (A.M.B.); (L.C.); (L.M.)
- Correspondence:
| | - Lucia Manzoli
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy; (A.F.); (A.D.S.); (S.M.); (S.R.); (A.C.); (A.M.B.); (L.C.); (L.M.)
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Volpe VO, Komrokji RS. Treatment options for lower-risk myelodysplastic syndromes. Where are we now? Ther Adv Hematol 2021; 12:2040620720986641. [PMID: 33505645 PMCID: PMC7812395 DOI: 10.1177/2040620720986641] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Accepted: 11/12/2020] [Indexed: 12/11/2022] Open
Abstract
Myelodysplastic syndromes (MDS) are a spectrum of clonal stem-cell disorders characterized clinically by bone-marrow failure. Resultant cytopenias are responsible for significant mortality and decreased quality of life in patients with MDS. In patients with low-risk MDS (LR-MDS), anemia is the most common cytopenia and erythropoiesis-stimulating agents (ESA) are usually used as first-line therapy. Those patients who become refractory to ESA have a poor survival. Available treatment options such as lenalidomide, hypomethylating agents, and immunosuppressive therapy can provide some hematologic response among selected subsets of patients, however durable responses are limited, and these agents can carry significant adverse effects. Chronic transfusions help to alleviate symptoms of anemia but still carry risks associated with transfusion and iron overload. Luspatercept, recently approved for those LR-MDS with ring sideroblasts refractory to ESA, was found to have an improvement in transfusion independence with a well-tolerated safety profile. While anemia is the most common cytopenia, thrombocytopenia and neutropenia management is challenging and the co-occurrence of these cytopenias with anemia may dictate the choice of therapy. In this article, we review LR-MDS and discuss the optimal use of current treatment options and explore new therapeutic options on the horizon.
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Affiliation(s)
- Virginia O. Volpe
- H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA
| | - Rami S. Komrokji
- H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
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Dunmore BJ, Jones RJ, Toshner MR, Upton PD, Morrell NW. Approaches to treat pulmonary arterial hypertension by targeting bmpr2 - from cell membrane to nucleus. Cardiovasc Res 2021; 117:2309-2325. [PMID: 33399862 DOI: 10.1093/cvr/cvaa350] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 11/06/2020] [Accepted: 12/15/2020] [Indexed: 12/12/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is estimated to affect between 10-50 people per million worldwide. The lack of cure and devastating nature of the disease means that treatment is crucial to arrest rapid clinical worsening. Current therapies are limited by their focus on inhibiting residual vasoconstriction rather than targeting key regulators of the cellular pathology. Potential disease-modifying therapies may come from research directed towards causal pathways involved in the cellular and molecular mechanisms of disease. It is widely acknowledged, that targeting reduced expression of the critical bone morphogenetic protein type-2 receptor (BMPR2) and its associated signalling pathways is a compelling therapeutic avenue to explore. In this review we highlight the advances that have been made in understanding this pathway and the therapeutics that are being tested in clinical trials and the clinic to treat PAH.
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Affiliation(s)
- Benjamin J Dunmore
- Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Royal Papworth Hospitals, Cambridge, UK
| | - Rowena J Jones
- Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Royal Papworth Hospitals, Cambridge, UK
| | - Mark R Toshner
- Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Royal Papworth Hospitals, Cambridge, UK
| | - Paul D Upton
- Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Royal Papworth Hospitals, Cambridge, UK
| | - Nicholas W Morrell
- Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Royal Papworth Hospitals, Cambridge, UK
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Abstract
Myelodysplastic syndromes (MDS) are clonal hematological disorders arising from hematopoietic stem cells that have accumulated various genetic abnormalities. MDS are heterogeneous in nature but uniformly characterized by chronic and progressive cytopenia from ineffective hematopoiesis, dysplasia in single or multiple lineages, and transformation to acute leukemia in a subset of patients. The genomic landscape revealed by next-generation sequencing has provided a comprehensive picture of the molecular pathways involved in MDS pathogenesis. Recurrent mutational targets in MDS are the genes involved in RNA splicing, DNA methylation, histone modification, transcription, signal transduction, cohesin complex and DNA repair. Sequential acquisition of mutations in these sets of genes serves as a driver for the initiation, clonal evolution and progression of MDS. Based on these findings, novel agents targeting driver mutations of MDS are currently under development and expected to improve the clinical outcome of MDS in the coming decades.
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Affiliation(s)
- Hideaki Nakajima
- Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Japan
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