ACVR1: A Novel Therapeutic Target to Treat Anemia in Myelofibrosis
by
, , , and
Andrea Duminuco
1,*,†
,
Helen T. Chifotides
2,†,
Sebastiano Giallongo
3
,
Cesarina Giallongo
3,
Daniele Tibullo
4
and
Giuseppe A. Palumbo
1,3 1
Hematology Unit with BMT, A.O.U. Policlinico “G.Rodolico-San Marco”, 95123 Catania, Italy
2
Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1400 Holcombe Blvd., Houston, TX 77030, USA
3
Department of Medical, Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, University of Catania, 95123 Catania, Italy
4
Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2024, 16(1), 154; https://doi.org/10.3390/cancers16010154
Submission received: 5 December 2023
/
Revised: 20 December 2023
/
Accepted: 21 December 2023
/
Published: 28 December 2023
(This article belongs to the Special Issue Molecular and Genetic Diagnosis and Targeted Therapy of Myeloproliferative Neoplasms)
Simple Summary
The human activin receptor type I (ACVR1) is a complex protein that regulates production of hepcidin on hepatocytes and red blood cells. Hepcidin is a small peptide that regulates iron metabolism and plasma iron levels. High hepcidin levels are associated with anemia, which is a hallmark of myelofibrosis. Myelofibrosis is a cancer of the bone marrow, characterized by fibrosis and anemia, splenomegaly, and systemic symptoms. Anemia and red blood cell transfusions negatively impact prognosis in myelofibrosis. Ruxolitinib and fedratinib (JAK inhibitors) may exacerbate anemia in myelofibrosis patients. Momelotinib and pacritinib are potent ACVR1 inhibitors that are preferable to treat cytopenic patients with myelofibrosis. In September 2023, momelotinib was approved as a treatment for anemic patients with myelofibrosis based on the phase 3 clinical trials SIMPLIFY-1 and MOMENTUM, which demonstrated the marked anemia benefits of momelotinib. Other ACVR1 inhibitors (e.g., zilurgisertib) are evaluated in early phase clinical trials as treatments for anemia in MF patients.
Abstract
Activin receptor type I (ACVR1) is a transmembrane kinase receptor belonging to bone morphogenic protein receptors (BMPs). ACVR1 plays an important role in hematopoiesis and anemia via the BMP6/ACVR1/SMAD pathway, which regulates expression of hepcidin, the master regulator of iron homeostasis. Elevated hepcidin levels are inversely associated with plasma iron levels, and chronic hepcidin expression leads to iron-restricted anemia. Anemia is one of the hallmarks of myelofibrosis (MF), a bone marrow (BM) malignancy characterized by BM scarring resulting in impaired hematopoiesis, splenomegaly, and systemic symptoms. Anemia and red blood cell transfusions negatively impact MF prognosis. Among the approved JAK inhibitors (ruxolitinib, fedratinib, momelotinib, and pacritinib) for MF, momelotinib and pacritinib are preferably used in cytopenic patients; both agents are potent ACVR1 inhibitors that suppress hepcidin expression via the BMP6/ACVR1/SMAD pathway and restore iron homeostasis/erythropoiesis. In September 2023, momelotinib was approved as a treatment for patients with MF and anemia. Zilurgisertib (ACVR1 inhibitor) and DISC-0974 (anti-hemojuvelin monoclonal antibody) are evaluated in early phase clinical trials in patients with MF and anemia. Luspatercept (ACVR2B ligand trap) is assessed in transfusion-dependent MF patients in a registrational phase 3 trial. Approved ACVR1 inhibitors and novel agents in development are poised to improve the outcomes of anemic MF patients.
